Nano-formulations in disease therapy: designs, advances, challenges, and future directions.

Introduction

Nano-formulations encompass drug particles at the nanoscale (1–1000 nm, preferably less than 500 nm) that are prepared using nanotechnology or developed as novel drug delivery systems by integrating drug particles with nano-formulations [ 1 – 3 ]. A brief history of nano-formulations within the fields of medicine and pharmacology dates to the 1960s (Fig. 1 ). In 1964, the structural characterization of liposomes was initially documented. Liposomes, vesicular structures formed by encapsulating drugs within phospholipid bilayers, are widely recognized for their excellent biocompatibility and biodegradability [ 4 ]. In 1971, Ryman et al . introduced the concept of employing liposomes as drug delivery vehicles, marking the beginning of research into nano-formulations [ 5 ]. Fig. 1 The historical development of nano-formulations (self-made image by authors)

In 1990, the first approved nano-formulation, Amphotericin B Liposome (trade name AmBisome ® ), was authorized for intravenous administration in Ireland to treat severe deep fungal infections, such as kala-azar, yeast infections, and coccidioidomycosis [ 6 ]. The pioneering PEGylated long-circulating liposomal drug, Doxil®, developed by Sequus Pharmaceuticals in the United States, received FDA approval for marketing in 1995, primarily indicated for advanced ovarian cancer, multiple myeloma, and HIV-associated Kaposi's sarcoma [ 7 ]. The first nanoparticle (NP) albumin-bound paclitaxel (Abraxane ® ) was approved by the FDA for marketing in 2005. It is indicated for the treatment of metastatic breast cancer (MBC) and pancreatic cancer (PC) [ 8 ]. Injectable paclitaxel-loaded polymeric micelles (Genexol ® PM), which received marketing approval in South Korea in 2007, represent the first polymeric nano-formulation approved for cancer therapy. Indications for Genexol ® PM include malignant tumors such as non-small cell lung cancer (NSCLC) and ovarian cancer (OC) [ 9 ]. In 2017, Vyxeos ® , a liposomal formulation that concurrently encapsulates cytarabine and daunorubicin, was approved for commercial use in the treatment of conditions such as therapy-related acute myeloid leukemia (T-AML) and AML with myelodysplasia-related changes (AML-MRC) [ 10 ]. In 2018, the groundbreaking small interfering RNA (siRNA) drug Onpattro™ was introduced to the market, specifically for the treatment of hATTR polyneuropathy [ 11 ]. In the same year, Caplacizumab, the world's first nanobody drug, was approved for the treatment of adult acquired thrombotic thrombocytopenic purpura (aTTP). This event heralded the inception of a novel era in the advancement of pharmaceutical nano-formulations [ 12 ]. Then, in 2021, messenger RNA (mRNA) vaccines, specifically mRNA-1273 and BNT162b2 (commercially known as Comirnaty ® ), were authorized for emergency use in combating COVID-19 [ 13 ].

In recent years, a growing number of successful nano-formulations have emerged, including representative drugs that have either received FDA approval for marketing or are currently in clinical trial stages. Merck's Emend™ (aprepitant), developed using nanocrystal technology, represents the first and only Neurokinin-1 (NK-1) receptor antagonist on the market [ 14 ]. Insmed Incorporated’s Arikayce ® employs liposome-encapsulated amikacin to enhance pulmonary drug concentration while mitigating systemic toxicity [ 15 ]. Pfizer’s Besponsa ® conjugates an anti-CD22 antibody with a cytotoxic drug to deliver targeted therapy against B-cell acute lymphoblastic leukemia cells [ 16 ].

Over the past decade, the advancement of nano-formulations has evolved from fundamental materials science to clinical applications. FDA-approved nano-formulations (such as Doxil ® , mRNA-LNP vaccines, etc.) have exhibited significant clinical efficacy. Concurrently, emerging technologies like stimulus-responsive nanocarriers, bionic nanoparticles, and multi-functional diagnostic-therapeutic integration platforms have propelled the evolution of personalized medicine. Notably, the incorporation of artificial intelligence-assisted (AI) design has established a novel paradigm for enhancing the precision and intelligence of nano-formulations. In particular, nano-formulations have been widely applied in modern medicine due to their unique physicochemical and biological properties, playing a significant role in various fields, including oncology, pulmonology, cardiology, endocrinology, dermatology, and ophthalmology (Fig. 2 ). However, the application of nano-formulations continues to encounter a multitude of challenges, such as quality control during large-scale production and long-term evaluations in vivo. This review provides an overview of the breakthroughs achieved in the application of nano-formulations for targeted delivery and disease diagnosis and treatment. It further examines the critical scientific issues bridging material innovation and clinical translation, while also exploring potential future development directions. Here, we elaborate on the application of novel nano-formulations in disease diagnosis and treatment based on disease classification, while analyzing the difficulties and challenges encountered during implementation. Such detailed and comprehensive research has been rigorously validated but remains rarely reported in the literature. Fig. 2 The application of nano-formulations in treating diverse diseases (self-made image by authors). A Design and synthesis. Synthesized nano-formulations can be categorized into four main types: liposomes, inorganic NP, polymer-based NP, and hybrid NP. B Action mechanisms. Action mechanisms of NPs primarily including cellular internalization, cytosolic delivery achieved through endosomal escape, and direct intracellular. C Molecular imaging. Nano-formulations play a pivotal role in disease diagnosis, encompassing modalities such as fluorescence imaging (FI), magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET). D Therapeutic applications. Nano-formulations find extensive applications in disease treatment across various medical specialties, including oncology, pulmonology, cardiology, endocrinology, dermatology, and ophthalmology

Design and synthesis of nano-formulations

Currently, nano-formulations used in pharmaceutical nano-formulations can be classified into liposomes, inorganic nano-formulations, polymer-based nano-formulations, and hybrid nano-formulations (Fig. 3 ). Various types of nano-formulations possess unique characteristics. For instance, liposomes, as vesicular nano-formulations, exhibit excellent biocompatibility and can enhance the stability, bioavailability, and distribution of drugs. In pharmaceutical formulations, liposomes represent a relatively mature and widely used nanocarrier technology. Inorganic nano-formulations as delivery systems primarily composed of inorganic substances and have garnered significant attention due to their unique electrical and optical properties, biocompatibility, and low cytotoxicity. Polymeric NPs consist of polymeric materials, including natural polymers, such as albumin and polysaccharides, or synthetic polymers like polylactic acid (PLA) and polyglycolic acid (PGA). Drugs are dissolved, encapsulated, or adsorbed within the polymeric NP matrix, essentially forming a homogenous system. Hybrid nano-formulations combine multiple materials or properties, aiming to improve drug delivery efficiency and therapeutic effectiveness [ 17 , 18 ]. Fig. 3 Different classes of nano-formulations. A liposomes: including ligand NP, ionic NP, responsive NP (containing magnetic NP, temperature NP, light NP, and pH NP), and long cycle NP; B inorganic nano-formulations: including silica NP, iron oxide NP, gold NP, and Quantum dot; C polymer nano-formulations: including polymer NP, polymersome NP, dendrimer, and polymer micelle; D hybrid nano-formulations: including lipid-polymer NP, lipid-inorganic NP, silica-polymer NP, and protein-drug NP

Compared with traditional drugs, nano-formulations significantly enhance their bioavailability. For example, the natural plant alkaloid Camptothecin (CPT) exhibits potent antitumor activity; however, its structural instability and insolubility limit its applications. CPT nano-formulations can effectively overcome these shortcomings [ 19 ]. Additionally, nano-formulations coated with synthetic polymers offer the advantage of shielding drugs from immune-mediated degradation [ 20 ]. Additionally, nano-formulations naturally possess a high surface area-to-volume ratio, and can be functionalized with various ligands, including receptors, or antigens, lactoferrin, and folic acid. These modifications improve their ability to cross biological barriers and actively target treatment sites, thereby enhancing therapeutic efficacy while reducing side effects [ 4 , 21 – 24 ]. Moreover, multifunctional stimuli-responsive nano-systems, engineered from stimuli-responsive materials, can selectively release therapeutic agents in response to specific environmental triggers at the disease site, significantly enhancing drug accumulation in the target tissue [ 25 ]. Besides, diagnostic molecules such as fluorescent dyes, contrast agents, and biomarker detection probes can be conjugated to or integrated with nano-formulations, thereby enabling the development of an integrated nano-system for diagnosis, treatment, and monitoring [ 26 ].

In the past decade, a promising biomimetic targeting strategy has attracted significant attention [ 27 , 28 ]. In the field of biomimetic membranes, cell membranes are predominantly sourced from various types of cells including cancer cells, neutrophils, leukocytes, natural killer (NK) cells, macrophages, red blood cells, or combinations thereof [ 29 – 32 ]. Besides intact cell membranes, extracellular vesicles (including exosomes, microvesicles, and apoptotic bodies) and various viral vectors originating from mammalian viruses, bacteriophages, and plant viruses also serve as natural membrane substrates [ 33 , 34 ]. These vectors interact with synthetic NPs or drug-loaded functional agents to form biomimetic NPs (BNPs) via diverse methodologies [ 35 ]. BNPs minimize adverse immune responses and avoid direct elimination, thereby prolonging their circulation time in the body [ 36 ]. Dendritic cell membrane-coated NPs loaded with drugs have demonstrated efficacy in both immunotherapy and immunoprevention in mouse models [ 37 ]. For example, Fe 3 O 4 -ICG@IRM, encapsulated within a hybrid biomimetic membrane derived from mouse ID8 ovarian cancer cells and red blood cell membranes and incorporating indocyanine green, demonstrates potential for the treatment of ovarian cancer [ 32 ].

Optimizing the physicochemical properties of nano-formulations can balance long circulation, targeting and biocompatibility, but the design needs to be adjusted according to specific applications (such as tumor delivery, gene therapy, etc.).The size of nano-formulations affects the distribution and removal. Nano-preparations with small particle size (< 10 nm) are easily cleared by glomerular filtration and may also penetrate the vascular endothelial space [ 38 ]. The nano-formulations with medium size (10–200 nm) are beneficial for prolongating blood circulation to avoid liver and spleen entrapment, thereby targeting tumor tissue through the enhanced permeability and retention (EPR) effect [ 39 ]. Nano-formulations with large particle size (> 500 nm) are easy to be phagocytosed by the reticuloendothelial system (RES) and are enriched in the liver and spleen [ 40 ]. In addition, the nano-formulations with 20–200 nm are more likely to enter cells through endocytosis; the nano-formulations with such as < 10 nm may be passive diffusion, and too large nanoparticle cannot be effectively eliminated [ 41 ].

Positively charged nano-formulations can bind to negatively charged cell membranes, thereby enhancing endocytosis efficiency. However, they may also increase non-specific adsorption, cytotoxicity, and plasma protein adsorption, which could modulate physicochemical interactions [ 42 , 43 ]. Thus, these nano-formulations can be expedited eliminated. The cycle time of negatively charged or neutral nano-formulations can be prolonged by minimizing electrostatic interactions with cell membranes. However, this may result in a weakened targeting effect [ 44 ]. Spherical nano-formulations are the most common type, characterized by ease of synthesis and high endocytosis efficiency [ 45 ]. Nano-formulations with a high aspect ratio (such as nanorods and fibers) have the potential to prolong blood circulation time; however, they are prone to being captured by the RES [ 46 ]. There is enhanced vascular wall adhesion or tumor-targeting in nano-formulations containing specifically shaped nano-formulations (e.g., disk-shaped). Irregularly shaped nano-formulations may elicit immune responses or cause mechanical damage [ 47 ].

In general, the combined effects of nano-formulations on biological interactions are multifaceted and complex. Pharmacokinetic factors, including particle size and surface charge, play critical roles in determining blood circulation time, tissue distribution, and clearance pathways. The EPR effects is dependent on an optimal range of particle size, while active targeting necessitates specific surface modifications, such as the conjugation of antibodies or ligands. Positively charged or excessively large nano-formulations may lead to inflammation or organ deposition, particularly in organs such as the liver and spleen. Additionally, the shape and charge of nanomaterials significantly influence the mechanisms of endocytosis (e.g. Clathrin vs. fossa pathway).

The design strategies for nano-formulations encompass targeted design, stimulus-responsive design, and multifunctional integration design. Targeted design includes (i) passive targeting, which capitalizes on the characteristics of the tumor microenvironment (such as increased vascular permeability and impaired lymphatic drainage) to enable nano-formulations to accumulate in tumor sites via the EPR effect; and (ii) active targeting, which involves modifying the surface of nanoparticles to enable them to specifically recognize and bind to target cells or tissues, thereby enhancing drug accumulation at the disease site [ 48 ]. In stimulus-responsive design, nano-formulations can release drugs in response to changes in pH, enzymes, or REDOX environments. Temperature-responsive systems utilize localized heating (such as through ultrasound or radiofrequency) to induce phase transitions or structural changes in the nanocarriers, leading to drug release. Additionally, ultrasound-sensitive nanosystems can be designed to trigger drug release through the radiative force or cavitation effects of ultrasound [ 49 ]. Multifunctional integration design integrates multiple therapeutic modalities (such as chemotherapy, radiotherapy, and immunotherapy) onto a single nanoscale platform to achieve synergistic therapeutic effects and enhance treatment efficacy. Furthermore, nano-formulations with both diagnostic (e.g., imaging) and therapeutic functionalities can be designed to enable theranostic applications [ 50 ].

The synthesis methods of nano-formulations encompass chemical synthesis, self-assembly, and solvent evaporation. Chemical synthesis methods include: (i) sol–gel method, which involves the hydrolysis and condensation reactions of metal alkoxides to form NPs; (ii) co-precipitation method, where multiple metal ions are simultaneously precipitated under controlled reaction conditions to form composite NPs; (iii) microemulsion method, utilizing surfactant-stabilized microemulsion droplets as nanoreactors for synthesizing NPs; and (iv) hydrothermal synthesis method, which employs aqueous solution-based chemical reactions under high temperature and pressure conditions to synthesize NPs [ 1 , 51 ]. Molecular self-assembly is a method that spontaneously forms nanostructures through intermolecular interactions such as electrostatic attraction, hydrogen bonding, π-π stacking, etc. Additionally, NP self-assembly involves controlling the surface chemical properties of NPs to induce their spontaneous assembly into nanomaterials with specific structures and functions [ 52 , 53 ]. The solvent evaporation method involves dissolving the drug in an organic phase (e.g., chloroform), emulsifying it with an aqueous phase, and then evaporating the organic solvent to form drug-loaded NPs [ 54 ]. In practical applications, it is necessary to select appropriate methods based on drug properties, nanomaterial types, and therapeutic requirements. For instance, the emulsion-solvent evaporation method is frequently employed for the nanonization of antibiotics, whereas the sol–gel method and hydrothermal synthesis are more suitable for the preparation of inorganic non-metallic nanomaterials [ 55 ].

Action mechanisms, metabolism and excretion of nano-formulations

Drug delivery via NPs primarily involves three approaches, including cellular internalization, cytosolic delivery achieved through endosomal escape, and direct intracellular, as presented in Fig. 4 . Fig. 4 Major NP-based delivery methods: A cellular internalization, B cytosolic delivery through endosomal escape, and C direct intracellular delivery

Nano-formulations, by binding ligands on their surfaces to specific receptors or other molecules onto the cell membrane, are internalized by cells through endocytosis and subsequently degraded via the endosome-lysosome transport pathway (Fig. 4 A). The lysosome is a critical cellular organelle that houses a diverse array of hydrolytic enzymes capable of degrading materials derived from both intracellular and extracellular sources. Nano-formulations are degraded by hydrolytic enzymes within the lysosome, leading to the loss of their original structure and function and the subsequent release of the encapsulated drug. However, NPs engineered with specific properties, such as modifications in size, shape, or surface chemistry, can evade degradation within the endosome/lysosome compartment and successfully translocate into the cytoplasm. This phenomenon is referred to as endosomal/lysosomal escape (Fig. 4 B). Once the NPs have escaped from the endosome and entered the cytoplasm, they can begin to release the drug. The mechanism of drug release can be diffusion-controlled, erosion-controlled, or stimulus-responsive, depending on factors such as the composition, structure, and method of drug loading.

In fact, nano-formulations can not only improve the solubility, pharmacokinetics and drug retention time of poorly soluble drugs but also enable controlled drug release through the stimulus-responsive properties of the carrier [ 56 – 58 ]. Direct intracellular delivery methods generally employ physical or chemical approaches to introduce NPs or their associated payloads directly into the cell interior (Fig. 4 C). These methods encompass microinjection, direct intracellular delivery, and membrane permeabilization. Moreover, its nanoscale dimensions enable more effective interaction with the biological environment. The EPR effect facilitates the migration of macromolecules up to 400 nm in diameter to the tumor site, thereby enabling passive targeting of the nano-preparations to the tumor cell [ 21 , 59 ]. Since its discovery in 1986, the EPR effect has served as a fundamental pillar in the advancement of cancer nano-therapy [ 60 ].

The metabolism and excretion of nano-formulations are the key factors that significantly influence their efficacy and safety. Owing to the distinctive physical and chemical characteristics of nano-formulations (e.g., small size, high surface area, modifiable surface functionality, etc.), the metabolic and excretory pathways of various nano-formulations markedly differ from those of conventional small-molecule drugs. Nano-formulations are typically metabolized through enzymatic degradation, redox reactions, and protein corona formation. In particular, some nano-formulations (e.g., liposomes, polymer nanoparticles) can be degraded into small molecule products by enzymes in the body (e.g., esterases, proteases) [ 61 ]. Metal-containing nanoparticles (e.g., gold, iron oxides) may be modified or decomposed through REDOX reactions. After the nanoparticles enter the blood, the surface will adsorb proteins to form a “protein crown”, which may change their original properties and affect metabolic pathways [ 62 , 63 ]. It should be noted that many nanomaterials (such as inorganic nanoparticles) metabolize slowly and may remain in the body for a long time in their original form.

Excretion of nano-formulations primarily depends on their size, material composition, and surface characteristics. Typically, nanoparticles with a hydrated diameter of less than 5–6 nm can be filtered by the glomerulus and subsequently excreted via urine [ 64 ]. Larger particles or rigid structures, such as carbon nanotubes, are challenging to excrete via renal filtration due to their size and structural properties. Nanoparticles with larger dimensions (e.g., 20–200 nm) are more likely to be internalized by liver Kupffer cells or hepatocytes, subsequently entering the intestine through bile secretion and being excreted in feces [ 65 , 66 ]. Particles with hydrophobic or negatively charged surfaces are more likely to be captured by the liver [ 38 ]. NPs are easily captured by mononuclear phagocytic system (MPS) such as liver, spleen, bone marrow) and remain for a long time, which may take months to slowly degrade and be excreted [ 67 ].

There are also notable challenges associated with the metabolism and excretion of nano-formulations. First, non-degradable nano-formulations may accumulate in the liver, spleen and other organs for a long time, and the potential toxicity needs to be evaluated [ 68 ]. Second, certain nano-formulations may activate the complement system or trigger inflammation [ 69 ]. In addition, patients with abnormal liver and kidney function may affect the excretion efficiency, and the dose needs to be adjusted [ 70 ]. Currently, imaging tracing techniques such as radiolabelling (e.g. 99m Tc), fluorescent labelling or mass spectrometry are used to monitor the distribution of nano-formulations in vivo in real time [ 71 – 73 ]. Metabolomics can also be used to analyze the effects of nano-formulation on endogenous metabolic pathways [ 74 ].

In summary, the metabolic and excretory processes of nano-formulations are highly influenced by their design parameters, including size, material composition, and surface modification. Fine-tuning these parameters can modulate their behavior in vivo, thereby achieving an optimal balance between efficacy and safety. Future research should prioritize investigating long-term retention effects and developing precise strategies for enhancing excretion.

Nano-formulations in treating cancers

Cancer poses one of the most significant public health challenges globally, with projections indicating approximately 30 million annual deaths from the disease by 2030 [ 75 ]. Traditional cancer treatments, including surgery, chemotherapy, and radiotherapy, have notably enhanced the survival rates of numerous patients. However, in the context of advanced metastatic cancer, their therapeutic efficacy is limited [ 76 ]. For many cancers, chemotherapy serves as the primary treatment option [ 77 ]. Nevertheless, conventional chemotherapy drugs are non-selective, causing indiscriminate damage to both tumor cells and normal cells, which often leads to toxic and adverse effects alongside therapeutic benefits. Furthermore, the emergence of multidrug resistance to these chemotherapy agents poses another significant challenge that cannot be overlooked [ 78 ]. Prolonging the survival and quality of life of patients by reducing the systemic toxicity of chemotherapy is the main goal of cancer treatment [ 79 ]. Therefore, investigating innovative therapeutic strategies, particularly nano-formulations that are both highly efficient and biologically safe, has emerged as a critical focus in cancer treatment.

Nano-formulations and cancer diagnosis

Early detection of cancer is essential for improving treatment outcomes and patient survival rates [ 80 ]. NPs have emerged as promising tools for the targeted delivery of diagnostic and chemotherapeutic agents to cancer cells. Nanodiscs (NDs), which are structurally analogous to high-density lipoproteins (HDLs), consist of nanoscale membrane bilayers encircled by amphiphilic molecules, including proteins, synthetic polymers, or short-chain lipids [ 81 ]. NDs with a nanoscale, disc-like morphology are readily amenable to conjugation with a variety of imaging agents [ 82 ]. Cancer cells exhibit elevated expression levels of specific receptors, including Scavenger Receptor Class B Type 1 (SR-B1), αvβ3 integrins, somatostatin receptors, folate receptors (FARs), and low-density lipoprotein (LDL) receptors [ 83 ]. NDs functionalized with specific tumor-targeting ligands chemically attached to their surface or edges can selectively target tumor cells, and have emerged as crucial tools for both diagnosis and treatment, as summarized in Fig. 5 . Fig. 5 Schematic model of nano-formulations and cancer diagnosis techniques. A Preparation process of indocyanine green (ICG)-loaded and cancer cell membrane-coated nanoparticles (ICNPs). B Schematic diagram illustrating isotope-targeted ICNPs utilized for dual-modal imaging-guided photothermal therapy. C Synthetic design of F/A-PLGA@DOX/SPIO nanoparticles and schematic representation of their application in tumor MRI Adapted from Chen Z, Zhao P, Luo Z, et al . Cancer Cell Membrane-Biomimetic Nanoparticles for Homologous-Targeting Dual-Modal Imaging and Photothermal Therapy. ACS Nano. 2016;10(11):10,049–57. Gao P, Mei C, He L, et al . Designing multifunctional cancer-targeted nanosystem for magnetic resonance molecular imaging-guided theranostics of lung cancer. Drug Deliv. 2018;25(1):1811–25.

Currently, a wealth of evidence demonstrates the efficacy of NDs in delivering diagnostic reagents across various imaging modalities, including fluorescence imaging (FI), magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET) [ 84 ]. SR-B1 is highly expressed in various cancers, including prostate cancer, breast cancer, and ovarian cancer [ 85 ]. Tang et al . developed synthetic HDL (sHDL) and its pegylated counterpart (PEG-sHDL), while comparing their tumor targeting capabilities with NDs possessing liposomes and pegylated liposomes (PEG-LIP). By incorporating hydrophobic fluorescent dyes as model drugs and tracers, the cellular uptake efficiency, tumor spheroid penetration, tumor accumulation, and in vivo distribution of all NDs were systematically evaluated. The results demonstrated that sHDL significantly enhanced SR-BI-mediated tumor targeting, penetration of tumor tissues, and accumulation in tumors [ 86 ]. Chen and co-workers developed gadolinium and fluorescent dye-loaded, Arg-Gly-Asp (RGD)-modified reconstructed high-density lipoprotein (rHDL-RGD) NPs, which were further functionalized with a cyclic pentameric RGD peptide specific to αvβ3 integrin, for the targeted delivery to angiogenic endothelial cells. The in vitro studies demonstrated that rHDL-RGD NPs were selectively internalized by endothelial cells. Both near-infrared (NIR) and MR imaging confirmed the accumulation of rHDL-RGD in mouse tumor models, demonstrating the potential of NDs for multimodal imaging of tumor-associated processes [ 87 ].

Additionally, magnetic NPs (MNPs) exhibit superparamagnetism and exceptional biocompatibility, making them ideal carriers for immunodiagnostics. Specifically, iron oxide-based MNPs have garnered FDA approval for clinical applications as contrast agents in MRI [ 88 ]. Gao et al . have developed a multifunctional drug-loaded targeted nanosystem (F/A-PLGA@DOX/SPIO) that not only promotes excessive production of reactive oxygen species (ROS) in A549 lung cancer cells, inducing apoptosis, but also serves as an excellent T 2 -negative contrast agent for MRI [ 89 ]. Cancer cell membrane-coated NPs (CCM-NPs) exhibited intrinsic tumor-homing properties, rendering them exceptionally suitable for diagnostic imaging and targeted phototherapy in cancer treatment. In another case, Chen et al . designed ICNPs consisting of an indocyanine green (ICG) polymer core encapsulated within a cancer cell membrane shell, enabling specific homologous targeting of cancer cells. Under near-infrared (NIR) laser irradiation, ICNPs effectively eliminated xenograft tumors via photothermal therapy (PTT) and concurrently demonstrated superior fluorescence/photoacoustic (FL/PA) imaging capabilities [ 31 ].

Nano-formulations and cancer metastasis

Epithelial-to-Mesenchymal Transition (EMT) is a cellular process wherein epithelial cells lose their polarized organization and intercellular junctions, undergo morphological and cytoskeletal reorganization, and acquire mesenchymal traits, including fibroblast-like morphology, enhanced migratory capacity, and invasive capabilities [ 90 ]. Various cytokines present in the tumor microenvironment can activate a series of intracellular signaling pathways, inducing the occurrence of EMT [ 91 ]. The abnormal activation of EMT is not only essential for early tumor migration but also promotes chemotherapy resistance and disease progression [ 92 ]. Bioactive natural compounds, including artemisinin, curcumin, luteolin, withaferin-A (WFA), and quercetin, have been demonstrated to target the EMT signaling pathway and inhibit the expression of specific biomarkers in both cell cultures and preclinical cancer models [ 93 ]. However, the limited water solubility and low bioavailability of natural compounds significantly restrict their clinical applications. Recently, nano-formulations have emerged as a promising carrier for delivering these compounds, as demonstrated in Fig. 6 . Fig. 6 Schematic model of nano-formulations and cancer metastasis

The conjugate of gold NPs (AuNPs) and quercetin (AuNPs-Qu-5) demonstrates a significant capability to reduce the expression of proteins associated with EMT and angiogenesis, while concurrently enhancing the expression of E-cadherin. AuNPs-Qu-5 not only inhibited the migration and invasion of breast cancer cells but also suppressed the growth of breast cancer tumors in rats [ 94 ]. Agarwalla et al . have developed a co-formulation named GNP-DSH-WFA by conjugating thiol-modified dexamethasone (a glucocorticoid) and WFA onto gold NPs [ 95 ]. This formulation exhibited remarkable efficacy in a mouse melanoma model, effectively reversing EMT in tumor cells. Furthermore, GNP-DSH-WFA markedly decreased the expression of ATP-binding cassette subfamily G member 2 (ABCG2), a protein frequently observed in cancer cells and strongly linked to the development of multidrug resistance. By downregulating ABCG2 expression, GNP-DSH-WFA enhances the sensitivity of cancer cells to chemotherapeutic agents, thereby improving treatment efficacy [ 95 ].

Recently, Baghi et al . have demonstrated that the combination of curcumin-loaded dendrosomal nanocurcumin (DNC) with exogenously delivered p53 significantly reduced the transcription levels of ZEB1 and BMI1 genes, which were associated with EMT and metastasis [ 96 ]. DNC, in combination with exogenous p53, demonstrated synergistic anticancer effects by significantly enhancing apoptosis and reducing migratory capacity in breast cancer MDA-MB-231 cells. In another study, Manisha and co-workers designed selenium NPs loaded with curcumin (Se-CurNPs), which exerted anticancer effects in colorectal cancer cells (HCT116) by enhancing autophagy and apoptosis levels, while significantly reducing the expression of EMT-related metastasis proteins (such as CD44 and N-cadherin) [ 97 ]. Furthermore, Se-CurNPs demonstrated a significant reduction in tumor burden in tumor-bearing mice and extended their average survival time [ 97 , 98 ]. Additionally, researchers have developed a bimetallic nano-formulation platform loaded with PtCl₂(OH)₂(NH₃)₂, utilizing pH-sensitive zeolite imidazolate framework-8 (ZIF-8) as a carrier. This nano-formulation inhibits the proliferation and invasion of tumor cells by interfering with inositol-1,4,5-trisphosphate-mediated cell communication [ 99 ].

Nano-formulations for cancer therapy

Compared to normal tissues, tumor tissues are distinguished by an abundance of newly formed, irregular blood vessels, wider interstitial spaces, and inadequate lymphatic drainage. These characteristics enhance the EPR effect, thereby facilitating high permeability and retention of macromolecules and lipid particles [ 100 ]. In addition, tumor cells and vascular endothelial cell surfaces frequently overexpress specific receptors, such as programmed cell death ligand 1 (PD-L1) and CD47. By conjugating specific ligands of these receptors, such as monoclonal antibodies, antibody fragments, peptides, and growth factors, to the surface of nano-formulations, active targeting of nano-formulations can be achieved [ 101 ]. Notably, this active targeting strategy leverages the EPR effect as its foundation. Therefore, anticancer drugs can be delivered to tumors via both passive tissue targeting and active cell-targeted approaches. Currently, nano-formulations have ushered in an unprecedented new era in cancer therapy through various approaches including chemotherapy, immunotherapy, modulation of the tumor microenvironment, gene therapy, and others (Fig. 7 ). Fig. 7 Nano-formulations and cancer treatment methods

The role of nano-formulations in chemotherapy

In the realm of cancer chemotherapy, nano-formulations are emerging as game-changers, offering unprecedented advantages and innovations (Fig. 8 ). The EPR effect facilitates the passive accumulation of nano-formulation in tumor tissues, thereby mitigating the side effects associated with chemotherapeutic agents. Targeted nano-formulations can selectively accumulate in tumor tissues, thereby enhancing therapeutic efficacy while minimizing the toxic and side effects associated with chemotherapy drugs. Taxanes, as prototypical microtubule-stabilizing agents, are widely employed in the treatment of breast cancer, lung cancer, and various other malignancies [ 102 ]. Docetaxel (DTX), a member of this family, frequently encounters limitations in clinical application owing to its poor solubility, non-specific distribution, and rapid clearance. Fig. 8 Nano-formulations in chemotherapy

Tan et al . have developed a series of novel triblock copolymers, MPEG-PDLLA-PLL, by introducing hydrophilic poly (L-lysine) (PLL) segments of different molecular weights into the monomethoxy poly (ethylene glycol)-poly (D, L-lactide) (MPEG-PDLLA) block copolymer [ 103 ]. The MPEG2k-PDLLA4k-PLL1k molecular chain could encapsulate up to 20% (w/w) DTX. The PDLLA segment (with a molecular weight of 4 kDa) forms a densely packed hydrophobic core, effectively encapsulating hydrophobic DTX molecules via hydrophobic interactions. This reduces drug release during blood circulation and prolongs the in vivo circulation time. The hydrophilic MPEG outer layer minimizes plasma protein adsorption and MPS clearance, thereby extending the micelles' residence time in the bloodstream. The positively charged PLL segment facilitates endocytosis by electrostatically interacting with negatively charged phospholipids in the tumor cell membrane, thus enhancing the intracellular delivery efficiency of DTX. The drug-loaded micelles exhibited high stability and demonstrated significantly enhanced inhibition of tumor cell growth, exhibiting superior anti-breast cancer efficacy. Xiao et al . have developed a novel borate cross-linked micelle (BCM) for loading paclitaxel (PTX) [ 104 ]. BCM demonstrated remarkable stability in both serum and plasma, exhibiting a significantly longer in vivo circulation time compared to non-cross-linked micelles (NCM). It released drugs in acidic environments or under the action of mannitol, and accumulated in tumors. In a mouse model of ovarian cancer, BCM-PTX preferentially accumulated in the tumor sites with a prolonged retention time, demonstrating superior therapeutic efficacy compared to NCM and PTX alone, while mice could tolerate higher doses of PTX.

It is important to highlight that in the majority of patients with advanced cancer, the EPR effect has not shown the anticipated therapeutic outcomes [ 105 , 106 ]. Given this context, the development of nano-formulations with tumor-targeting capabilities to optimize the delivery of anticancer drugs is of particular importance. Wang et al . designed polymer micelles composed of 2-hydroxypropyl methacrylamide (HPMAm) and functionalized with biotin for the targeted delivery of PTX. Biotin receptor-mediated endocytosis facilitated the NPs to exhibit enhanced cytotoxicity of PTX in A549 lung cancer cells [ 107 ]. Heat shock protein 90 (HSP90), which is markedly overexpressed in a variety of cancers, facilitates the maturation of multiple oncogenic proteins and thereby promotes cancer cell proliferation [ 108 ]. Jia et al . designed HSP90 and CD44-targeted A6 peptide-functionalized biomimetic NPs (A6-NP) for the delivery of the HSP90 inhibitor G2111 [ 109 ]. A6-NP is straightforward to prepare, demonstrates excellent biocompatibility, and facilitates the controlled release of G2111, thereby minimizing off-target toxicity. A6-NP exhibits remarkable targeting capability and anticancer efficacy against hematological malignancies and colon cancer both in vitro and in vivo.

Furthermore, biomimetic membrane-based nano-formulations have been extensively utilized for the delivery of chemotherapy drugs. Cellular membranes as nano-formulations have attracted considerable attention for their capability to evade clearance by the reticuloendothelial system (RES) and facilitate precise tumor-targeted delivery [ 110 ]. For instance, Li et al . developed a biomimetic nanodrug delivery system for the targeted therapy of colorectal cancer, comprising a PTX-loaded gelatin nanogel core encapsulated within an HT-29 tumor cell membrane shell [ 111 ]. This system featured a core–shell nanostructure, which effectively minimized premature drug release and achieved selective targeting. Consequently, it significantly enhances the accumulation of PTX at the tumor site, markedly inhibits tumor growth, and demonstrates minimal side effects.

The role of nano-formulations in immunotherapy

Cancer immunotherapy leverages the body's immune system to elicit a robust anti-tumor response, thereby mitigating tumor evasion. It has emerged as an indispensable and transformative approach in cancer treatment [ 112 ]. Immunotherapy encompasses immunosuppressive therapy, adoptive cell therapy (ACT), tumor vaccine therapy, oncolytic virotherapy, and monoclonal antibody (MAB) therapy [ 113 ]. These therapies exhibit reduced side effects compared to conventional radiotherapy and chemotherapy, thereby enabling extended progression-free survival (PFS) and overall survival (OS) for patients. However, every coin has two sides. An overly active immune system can lead to severe adverse reactions, including immune-mediated inflammatory responses, autoimmune diseases, opportunistic infections, demyelinating disorders, and hypersensitivity reactions [ 114 , 115 ]. This undoubtedly poses additional challenges on the path to treatment. In this context, nano-formulations shine like a beacon, illuminating a new direction for cancer immunotherapy.

Nano-formulations can enhance the efficacy of tumor immunotherapy, offering a potentially safer and more effective therapeutic approach [ 116 , 117 ]. Many immunotherapeutic drugs struggle to achieve optimal efficacy due to their hydrophobicity, but nano-formulations can substantially improve the solubility and bioavailability of these drugs, thereby enhancing their therapeutic efficacy. Even more excitingly, nano-formulations exhibit sustained-release and controlled-release properties, which are crucial for achieving continuous dosing and prolonged therapeutic responses in tumor immunotherapy. Furthermore, nano-formulations can intelligently respond to the unique physiological characteristics of the tumor microenvironment. For instance, smart responsive nano-formulations, such as temperature-sensitive and pH-sensitive carriers, can flexibly adjust drug release according to changes in the tumor microenvironment. This "tailor-made" treatment approach demonstrates tremendous application potential. Currently, the application of nano-formulations in tumor immunotherapy is in full swing (Fig. 9 ). Fig. 9 Nano-formulations in immunotherapy

Immune checkpoint inhibitors (ICIs)

T cells serve as the primary effector cells in tumor elimination, while ICIs can inhibit T cell proliferation and compromise their functionality [ 118 ]. Programmed cell death protein 1 (PD-1) and its ligand, PD-L1, serve as critical immune checkpoint molecules [ 119 ]. PD-1 inhibitors, such as pembrolizumab, have achieved significant efficacy in treating a range of malignancies, including NSCLC, melanoma, and hodgkin lymphoma (HL) [ 120 ]. These drugs function by inhibiting the interaction between PD-1 and PD-L1, thereby releasing T cells from the suppressive effects exerted by tumor cells and reinstating their antitumor activity. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is also a crucial immune checkpoint that functions to downregulate immune responses [ 121 ]. CTLA-4 inhibitors, such as ipilimumab, enhance antitumor immune responses by blocking the inhibitory signaling pathways of immune cells [ 122 ].

Dual ICI therapy, which combines two immune checkpoint inhibitors, has achieved significant results in various types of tumors. For instance, the combination therapy of Nivolumab (a PD-1 inhibitor) and Ipilimumab (a CTLA-4 inhibitor) has demonstrated remarkable efficacy in multiple tumor types, including melanoma, colorectal cancer (CRC), and NSCLC [ 123 – 125 ].

Protein hydrolysis-targeting chimeras (PROTACs) represent an innovative strategy for the selective degradation of proteins associated with tumors [ 126 ]. PROTACs generally comprise three key components: a small molecule that specifically binds to the protein of interest (POI), an E3 ligase ligand, and a linker [ 127 ]. However, challenges such as insufficient cellular internalization hinder PROTACs from effectively reaching their target sites and exerting their intended effects [ 128 ]. Based on these findings, researchers have engineered pH/cathepsin B sequentially responsive NPs (PSRNs) conjugated with PROTACs targeting cyclin-dependent kinases 4 and 6 (CDK4/6), leveraging ultra-pH-sensitive and enzyme-responsive nanotechnology [ 129 ]. PSRNs retain their nanostructure (approximately 40 nm) during circulation and accumulate in tumors via the EPR effect. In the acidic tumor microenvironment, they degrade into monomers (less than 10 nm), which enhances their tumor penetration and cellular internalization capabilities. Subsequently, PROTAC is released through enzymatic action. PSRNs not only enhance the degradation of target proteins both in vitro and in vivo in colorectal cancer (CRC) but also augment the efficacy of immune checkpoint blockades (ICBs) by upregulating PD-L1 expression in cancer cells and inhibiting regulatory T cell proliferation within the tumor microenvironment, thereby achieving enhanced anti-tumor effects in the CT26 tumor model [ 129 ].

CAR-T

ACT is an advanced immunotherapy approach that entails the isolation of autologous or allogeneic immune cells, followed by their activation or genetic modification in vitro. This process aims to enhance the antitumor efficacy of these cells before reinfusion into patients. This process is designed to expand immune cells that exhibit antitumor activity, which are subsequently reinfused into the patient to augment their antitumor immune response. ACT includes a variety of approaches, with chimeric antigen receptor T cell immunotherapy (CAR-T) receiving considerable attention in recent years.

CAR-T cell therapy is an innovative approach that involves genetically engineering patients' own T cells to express chimeric antigen receptors (CARs), which are designed to specifically recognize tumor-associated antigens [ 130 ]. These engineered T cells are subsequently expanded ex vivo and reinfused into the patients. The CAR-expressing T cells can specifically recognize and bind to target cell surface molecules, leading to the destruction of these cells. CAR-T cell therapy has demonstrated significant efficacy in the treatment of hematological malignancies and select solid tumors [ 130 , 131 ].

Researchers have conjugated protein nanogels (NGs) loaded with the interleukin-15 superagonist complex (IL-15Sa) to the surface of T-cells, while simultaneously facilitating the fusion of these carrier cells into solid tumors [ 132 ]. Subsequent activation of the T-cell receptor (TCR) triggered the release of IL-15SA adjuvants, leading to a 16-fold increase in T-cell expansion relative to systemically injected IL-15SA.This significantly enhances the tumor-suppressing effect. The anti-Tcrl-15SA nanogel backpack method has significantly improved the efficacy and safety of human CAR-T cell therapy in treating mouse tumors [ 132 ]. Recently, researchers have engineered a biohybrid consisting of IL-12 nanostimulant-integrated CAR T cells (INS-CAR T). In the presence of tumor antigens, the increased thiol groups on the cell surface induce the release of IL-12 from the INS-CAR T biohybrid. This, in turn, promotes the secretion of chemokines (CCL5, CCL2, and CXCL10), which selectively recruit and expand CD8 + CAR T cells within the tumor. The IL-12 nanochaperone significantly enhances the antitumor capabilities of CAR T cells, leading to the elimination of solid tumors with minimal side effects [ 133 ].

MAB

MAB therapy inhibits tumor growth by directly binding to tumor antigens or modulating cell signaling pathways. In targeted cancer therapy, monoclonal antibodies are extensively utilized owing to their high specificity and potent anti-tumor efficacy [ 134 ]. Epidermal growth factor receptor (EGFR), prostate-specific membrane antigen (PSMA), and human epidermal growth factor receptor 2 (HER2) have emerged as three prominent targets for MAB-functionalized NPs in cancer therapy, which have been extensively investigated in recent years [ 134 – 136 ]. By conjugating NPs loaded with chemotherapy or radiotherapy agents to monoclonal antibodies, tumor cells can be specifically targeted and attacked [ 134 ], thereby achieving enhanced specificity and reduced toxicity. Researchers have prepared rapamycin-loaded poly (lactic-co-glycolic acid) (PLGA) NPs (NPGA) with EGFR antibodies conjugated to their surfaces. This modification resulted in a more than 13-fold increase in uptake by MCF-7 cells compared to unconjugated NPs, thereby significantly enhancing the antitumor efficacy of the drug [ 137 ]. Saniee et al . conjugated glutamic acid-urea-lysine, a PSMA enzyme inhibitor, with poly (lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) NPs for the targeted delivery of docetaxel to prostate cancer cells, thereby enhancing the antitumor efficacy of docetaxel [ 138 ]. To further enhance the therapeutic efficacy of anticancer drugs, MAB can be conjugated with cytotoxic agents, forming antibody–drug conjugates (ADCs) [ 139 ]. Trastuzumab (Herceptin ® ) is a MAB used for the treatment of breast cancer with HER2 positive expression. Studies have been conducted using trastuzumab (Tmab) in ADC systems, and the results have shown improved therapeutic effects compared to the use of Tmab alone [ 140 ]. Researchers have conjugated Tmab to PLGA-PEG/PLGA NPs encapsulating docetaxel, facilitating sustained, controlled, and targeted release of docetaxel specifically into breast cancer cells [ 141 ]. Recently, researchers have developed a nano-formulation comprising a PTX-loaded core and a surface modified with Tmab. Experimental results demonstrate that the novel NP complex exhibits superior antitumor efficacy compared to PTX or Tmab alone, with relatively lower cytotoxicity observed in human breast epithelial cells used as a control group for the NP complex [ 142 ].

Nano-vaccines

Nano-vaccines leverage nanomaterials as carriers for the targeted delivery of specific antigens and adjuvants, demonstrating significant efficacy in disease prevention and treatment, particularly in influenza prophylaxis and cancer therapy. Tumor vaccines constitute an immunotherapeutic strategy that activates the patient's own immune system to eliminate or control tumor growth. The size of NPs, comparable to that of pathogens, facilitates efficient uptake by antigen-presenting cells (APCs).

Recently, researchers have developed a hybrid mRNA delivery platform (MnLNPs) by co-assembling manganese oxide NPs (Mn 3 O 4 NPs) with lipid NPs (LNPs). This innovative approach aims to enhance the efficacy of mRNA vaccines [ 143 ]. Mn 3 O 4 NPs exhibited potent capabilities in scavenging ROS and generating oxygen, thereby increasing intracellular ATP levels and improving mRNA translation efficiency. Furthermore, Mn 2+ activated the cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway, thereby promoting dendritic cell (DC) maturation and type I interferon secretion. This activation subsequently enhanced both innate and adaptive immune responses. The combination of MnLNPs@mRNAE7 vaccine with anti-PD-L1 antibody (αPD-L1) has reprogrammed the immunosuppressive tumor microenvironment, further augmenting the antitumor effect [ 143 ].

Cytotoxic T lymphocytes (CTLs) initiate an immune response against tumor cells by recognizing tumor-associated antigen peptides presented by MHC-I molecules on the cell surface [ 143 ]. However, tumor antigens must be processed by antigen-presenting cells (such as dendritic cells) prior to presentation by MHC-I molecules. This process encompasses endocytosis, proteasomal degradation, and the loading of peptide fragments onto MHC-I molecules [ 144 , 145 ]. The efficiency of antigen processing and presentation directly impacts the extent of CTL activation, consequently influencing the magnitude of the immune response. Tumor cells can evade immune system surveillance through multiple mechanisms, such as the downregulation of MHC-I molecule expression or the secretion of immunosuppressive factors [ 146 ]. Tumor vaccines are designed to augment the immune system's capability to recognize and target tumors through the presentation of tumor-specific antigens, thereby eliciting a more robust and specific antitumor immune response. Vaccines can activate the immune system, particularly CTLs, through various strategies such as the use of tumor cells, tumor antigen peptides, DNA, or mRNA [ 147 ]. Lipid NPs (LNPs) function as efficient vaccine delivery systems by enhancing antigen stability and promoting more effective uptake by immune cells [ 148 ].

Recently, researchers have developed an innovative tumor vaccine strategy termed TAgD-TVac. This approach harnesses targeted antigen degradation to augment antigen processing and cross-presentation. By pre-conjugating tumor antigens with E3 ubiquitin ligase ligands and encapsulating them within lymph node-targeting LNPs, TAgD-TVac successfully enhanced the degradation efficiency and cross-presentation of tumor antigens. This led to improved CTL activation and significantly inhibited tumor growth, metastasis, and recurrence in various cancer models, including melanoma, triple-negative breast cancer, Lewis lung cancer, and ovarian cancer. When used in conjunction with immune checkpoint inhibitors, a synergistically enhanced therapeutic effect was observed [ 149 ].

The role of nano-formulations in remoulding the tumor microenvironment (TME)

TME represents a complex ecosystem composed of tumor cells, immune cells, neuronal cells, vascular cells, and the extracellular matrix, playing a crucial role in tumor growth, invasion, metastasis, and response to treatment [ 150 , 151 ]. Studies have demonstrated that the interaction between the nervous system and tumors significantly influences tumor development and progression. Specifically, the density of tumor-associated nerves is closely correlated with both tumor size and patient survival rates [ 152 – 154 ]. Tropomyosin receptor kinase (TRK), a receptor tyrosine kinase expressed in both the peripheral and central nervous systems, plays an essential role in promoting neuronal growth and regulating synaptic plasticity [ 155 ]. Activation of TRK in the TME not only promotes neuronal growth but also enhances the proliferation and migration of tumor cells. Tumor-associated macrophages (TAMs), which exhibit dual roles within TME, can polarize into either M1 (anti-tumor) or M2 (tumor-promoting) phenotypes. Notably, M2-polarized TAMs are closely associated with nerve infiltration and play a significant role in promoting tumor growth and facilitating immune evasion.

Although chemotherapy drugs such as gemcitabine are the primary means of treating pancreatic cancer, they may inadvertently promote neuronal growth, which can potentially support tumor progression. Outer membrane vesicles (OMVs), a type of nanocarrier with high tumor-targeting efficacy, not only activate immune responses but also modulate the polarization state of AMs [ 156 ]. Utilizing nano-formulations for the delivery of the TRK inhibitor larotrectinib can enhance its concentration within the TME while minimizing adverse effects on normal tissues.

Researchers have reported a novel nanocarrier, Lar@NP-OMVs, which integrates OMVs with the neuropeptide NP41 and encapsulates larotrectinib. Lar@NP-OMVs can efficiently target tumor-associated nerves, reducing neurite outgrowth by blocking the neurotrophic factor/Trk signaling pathway. Furthermore, through OMV-mediated polarization of TAMs, Lar@NP-OMVs not only induce neurotoxicity but also effectively inhibit the proliferation, migration, and angiogenesis of pancreatic cancer cells. Furthermore, the combination of Lar@NP-OMVs with gemcitabine mitigates the latter's promotion of nerve infiltration and neurite outgrowth, thereby enhancing the efficacy of chemotherapy [ 157 ].

The role of nano-formulations in gene therapy

Nano-formulations serve as crucial vehicles in gene delivery and are essential non-viral vectors for gene therapy applications, as presented in Fig. 10 . By using nanotechnology, therapeutic genes or gene vectors can be accurately delivered to target cells or tissues for gene correction, gene amplification, gene inactivation or immunotherapy [ 158 ]. This approach is characterized by accurate targeting, high-efficiency delivery, minimal toxicity, and superior biocompatibility. siRNA can induce sequence-specific cleavage of mRNA molecules, resulting in their degradation. This mechanism is widely employed for the silencing or downregulation of gene expression. siRNA can be delivered through various nano-formulations, including LNPs, metal NPs, and silicon dioxide NPs, among others [ 158 ]. eIF4E, functioning as an oncogene, is implicated in tumorigenesis upon its overexpression or activation. Researchers have designed and developed a dual pH-sensitive LNP that can effectively inhibit eIF4E, thereby restoring the sensitivity of triple-negative breast tumors to paclitaxel treatment [ 159 ]. Messenger RNA (mRNA) constitutes a category of nucleic acid-based therapies employed for genome editing and the treatment of genetic disorders. Among these tools, CRISPR/Cas9 emerges as an exceptionally powerful and precise instrument for genome editing. By precisely modulating the interaction between phenylboronic acid (PBA)-derived LNPs and sialic acid (SA) on the cell surface, researchers have successfully delivered CRISPR/Cas9 into cancer cells, enabling selective genome editing. Experimental findings demonstrate that PBA-BDAP possesses the ability to specifically target and deliver P53 mRNA to cancer cells, thereby exerting an inhibitory effect on tumor cell proliferation [ 160 ]. Fig. 10 Schematic model of nano-formulations in gene therapy. A Design and schematic representation of pH-sensitive PEG(HZ)-ECO/siRNA dual nanoparticles. B Assembly schematic of PBA–BADP/mRNA nanoparticles for mRNA delivery and genome editing Adapted from Gujrati M, Vaidya AM, Mack M, et al . Targeted Dual pH-Sensitive Lipid ECO/siRNA Self-Assembly Nanoparticles Facilitate In Vivo Cytosolic sieIF4E Delivery and Overcome Paclitaxel Resistance in Breast Cancer Therapy. Adv Healthc Mater. 2016;5(22):2882–95. Tang Q, Liu J, Jiang Y, et al. Cell-Selective Messenger RNA Delivery and CRISPR/Cas9 Genome Editing by Modulating the Interface of Phenylboronic Acid-Derived Lipid Nanoparticles and Cellular Surface Sialic Acid. ACS Appl Mater Interfaces. 2019;11(50):46585-90

Exosomes are lipid-encapsulated vesicles that are rich in lipids, nucleic acids, proteins, and other bioactive molecules. As natural nano-formulations for therapeutic drug delivery, exosomes have been extensively studied. They can deliver a wide range of therapeutic agents, including small-molecule anticancer and anti-inflammatory drugs, proteins, and nucleic acids such as siRNA and miRNA [ 161 ]. Owing to the presence of lipids and molecules on the exosome membrane that resemble those of their parent cells, exosome NPs are capable of evading immune surveillance and efficiently internalizing into target cells [ 162 ].

Researchers utilized exosomes loaded with doxorubicin (DOX) (exoDOX) to treat human breast cancer cells. Experimental results demonstrated that, compared to free DOX, exoDOX not only enhanced the cytotoxicity of doxorubicin but also but also effectively reduced drug accumulation in the heart [ 163 ]. Recently, researchers have demonstrated the significant antitumor efficacy of cholesterol-rich exosomes in delivering PLK1 siRNA in colorectal cancer models. The cholesterol-enriched milk-derived exosomes (MEs), with a 30% cholesterol enhancement, directly release siRNA via membrane fusion, thereby significantly inhibiting tumor growth, promoting cell apoptosis, and reducing tumor metastasis. Moreover, experimental evidence has shown that MEs exhibit favorable in vivo safety profiles and low immunogenicity, indicating their potential value in cancer therapy [ 164 ].

The role of nano-formulations in other therapies

Photodynamic therapy (PDT) and PTT have emerged as promising cancer treatment modalities in recent years, both of which are categorized under phototherapy [ 162 ]. PDT entails the targeted accumulation of photosensitizers in tumor regions via specialized methods. Subsequently, upon irradiation with light of a specific wavelength, the photosensitizers become activated, producing singlet oxygen and other cytotoxic ROS [ 165 ]. These reactive species effectively induce apoptosis or necrosis in tumor cells, thereby achieving the therapeutic objective. In comparison, PTT emphasizes the use of materials with high photothermal conversion efficiency. When exposed to light, these materials efficiently convert light energy into thermal energy, leading to a substantial increase in the temperature of the targeted tumor region [ 166 ]. The high-temperature environment is lethal to cancer cells, inducing their apoptosis and thereby enhancing therapeutic efficacy.

To enhance anti-tumor efficacy, a synergistic approach combining siRNA drugs with PTT is employed for the treatment of prostate cancer cells. In particular, gold nanorods (Au NRs) functionalized with zinc(II)-dipicolylamine are utilized as carriers for siPLK, which specifically inhibits the expression of polo-like kinase-1 (PLK1) in cancer cells, thereby forming innovative NPs. These NPs effectively inhibit PLK1, thereby reducing the viability and proliferative activity of cancer cells. Moreover, the NPs demonstrate pronounced anti-tumor efficacy upon laser irradiation in both PC-3 cell lines and PC-3 tumor-bearing mice models [ 167 ]. Fullerenes, as a type of nanomaterial, exhibit outstanding performance in both PDT and PTT [ 168 , 169 ]. Researchers have developed a type of near-infrared light-excited NP that leverages photoacoustic imaging to achieve both photothermal and PDT effects on tumors. Compared to fullerenes and DOX, this NP demonstrates superior ROS generation and heat production. Both in vitro and in vivo studies have consistently shown that the synergistic combination of PDT and PTT effectively inhibits tumor growth [ 169 ].

Currently, it is gratifying to note that clinical trials of nano-formulations for tumor treatment are currently underway (Table 1 ). Table 1 Clinical trials for cancer treatment via nano-formulations Name Description Nanocarrier Indication Status Ref CYL-02 CYL-02 plus gemcitabine Polyethyleneimine Pancreatic ductal adenocarcinoma Phase 2 NCT02806687 Nano-SMART AGuIX Gadolinium-based NPs with stereotactic magnetic eesonance-guided adaptive radiation therapy AGuIX Pancreatic and Lung Cancer Phase 1/2 NCT04789486 Pembrolizumab(Pbr)/Nab-Paclitaxel Pbr/Nab-Paclitaxel followed by Pbr/Epirubicin/Cyclophosphamide Nab-paclitaxel Triple negative breast cancer Phase 2 NCT03289819 BCMA nano-antibody CAR-T cells Study the safety and efficacy of BCMA nano-antibody CAR-T in MM therapy Nano-antibody Multiple myeloma Phase 1 NCT03661554 Nano-Quercetin Quercetin versus its encapsulated NPs PLGA-PEG NPs Squamous cell carcinoma Phase 2 NCT05456022 Oral Nanocurcumin Adjuvant therapy NPs Anogenital warts Phase 2/3 NCT06281353

Nano-formulations and drug resistance

Despite remarkable progress in the development and application of chemotherapy drugs, multidrug resistance (MDR) continues to pose a significant barrier to effective treatment. Repeated or multiple administrations of chemotherapeutic drugs can lead to the emergence of MDR in tumor cells, thereby diminishing therapeutic efficacy [ 170 ]. MDR refers to the phenomenon where tumor cells acquire resistance not only to a specific antitumor drug but also exhibit cross-resistance to multiple other antitumor agents with distinct structures and mechanisms of action [ 171 ]. The mechanisms underlying MDR primarily include six aspects (Fig. 11 ): (i) overexpression of membrane transporter proteins, specifically ATP-binding cassette (ABC) proteins, which reduces drug influx and increases drug efflux in tumor cells; (ii) mutations in the target molecules of drug action that prevent drug binding; (iii) alterations in the metabolic enzyme system that either inactivate drugs or convert them into non-toxic forms; (iv) sequestration of chemotherapeutic drugs within vesicles by resistant tumor cells, followed by their expulsion through exocytosis; (v) enhanced DNA repair capabilities in tumor cells that confer resistance to chemotherapeutic drugs; (vi) upregulation of anti-apoptotic factors in tumor cells to inhibit drug-induced apoptosis [ 172 , 173 ]. By modulating multiple signaling pathways simultaneously, NP co-delivery therapy shows significant potential in overcoming MDR, thereby enhancing the efficacy of disease treatment, as presented in Fig. 12 . Fig. 11 Mechanisms of nano-formulations and drug resistance Fig. 12 Schematic model of nano-formulations and multidrug resistance. A The triple-payload delivery platform (HA-HNRplex) adopts a "kill three birds with one stone" strategy, enabling synchronous delivery of PTX, DSF, and Cyt C for the treatment of multidrug-resistant cancers. B Monoclonal antibody MDR1-modified chitosan nanoparticles (CNPs) can overcome acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) across various antitumor targets. C Chemical structure, transformation behavior, and schematic representation of a lysosomal pH-responsive small-molecule-based nanotransformer designed to overcome autophagy-induced drug resistance in cancer Adapted from Zou J, Xing X, Teng C, et al . Cocrystal@protein-anchoring nanococktail for combinatorially treating multidrug-resistant cancer. Acta Pharm Sin B. 2024;14(10):4509–25. Zheng Y, Su C, Zhao L, et al . mAb MDR1-modified chitosan nanoparticles overcome acquired EGFR-TKI resistance through two potential therapeutic targets modulation of MDR1 and autophagy. J Nanobiotechnology. 2017;15(1):66. Ma Z, Lin K, Tang M, et al . A pH-Driven Small-Molecule Nanotransformer Hijacks Lysosomes and Overcomes Autophagy-Induced Resistance in Cancer. Angew Chem Int Ed Engl. 2022;61(35):e202204567

Zheng et al . prepared chitosan NPs conjugated with MDR1 antibodies, encapsulating both gefitinib and the autophagy inhibitor chloroquine [ 174 ]. These NPs specifically bind to cells overexpressing MDR1, thereby enhancing their internalization. By modulating autophagy and concurrently inhibiting MDR1-mediated drug efflux, the intracellular concentration of gefitinib is significantly increased. Recently, Zou and co-workers developed a nano-formulation (HA-HNRplex) with a triple payload of MDR inhibitor (DSF), biological macromolecule apoptosis promoter (Cyt C), and PTX through the cocrystal@protein anchoring strategy [ 172 ]. HA-HNRplex exhibited high encapsulation efficiency and induced the apoptosis in MDR cells through a cascade mechanism that includes inhibition of P-gp, an ABC transporter implicated in MDR, elevation of intracellular cytochrome C levels, and upregulation of cleaved caspase-3 expression. HA-HNRplex demonstrates anti-MDR and anti-tumor effects on both normal and drug-resistant tumor cells, effectively treating cancer in A549/Taxol drug-resistant tumor-bearing mice.

Autophagy is a critical lysosome-dependent pathway responsible for recycling damaged macromolecules and organelles, which ultimately contributes to cancer cell survival and treatment resistance [ 175 ]. With the deepening understanding of the mechanisms underlying multidrug resistance (MDR), researchers have initiated explorations into lysosome-targeted MDR treatment strategies. By modulating lysosomal function or inhibiting specific active substances within them, it is possible to influence the formation and progression of MDR mechanisms, thereby enhancing the efficacy of chemotherapy drugs and mitigating drug resistance. Ma et al . have reported a nonpeptide PBC (pheophorbide a-bisaminoquinoline conjugate) targeting lysosomes [ 176 ]. At physiological pH, PBC self-assembles into NPs and subsequently transforms into nanofibrils within the lysosomes of tumor cells. This transformation resulted in lysosomal dysfunction, inhibition of autophagy, and abnormal cytoplasmic vacuolation. Furthermore, PBC-mediated photodynamic therapy could overcome the therapeutic resistance induced by intrinsic autophagy that is inherent in traditional photodynamic therapy.

Nano-formulations: putative strategies to treat pulmonary disease

Pulmonary disease, such as chronic obstructive pulmonary disease (COPD) and asthma, significantly impair patients' quality of life [ 177 ]. The treatment of respiratory diseases poses significant challenges, primarily due to insufficient dosing of drugs delivered to the respiratory tract or the inadequate targeting capability of conventional medications in reaching the affected areas [ 178 , 179 ].

Inhalable nano-formulations have exhibited remarkable advantages and considerable potential in the treatment of lung diseases (Fig. 13 ). They can overcome physiological barriers and enhance the deposition efficiency of aerosols in the lungs, thereby achieving precise drug delivery to the diseased sites within the lungs [ 178 , 180 ]. Drug formulations developed via nanotechnology can enhance drug solubility, improve stability and bioavailability, thereby significantly boosting therapeutic efficacy [ 181 ]. Nano-formulations facilitate targeted drug delivery, thereby reducing the required dosage and minimizing both toxicity and side effects associated with the drugs [ 182 , 183 ]. The sole inhalable nano-formulation currently available on the market is amikacin liposome inhalation suspension (Arikayce®), which received FDA approval in 2018 [ 184 ]. Arikayce® utilizes charge-neutral liposomes to encapsulate amikacin, thereby protecting the drug from rapid clearance by alveolar macrophages and extending its retention time in the lungs [ 185 ]. Via the eFlow nebulization system, Arikayce ® ensures effective deposition of the drug at the site of infection [ 185 ]. In the pulmonary environment, amikacin is released in a controlled and sustained manner, which helps to maintain therapeutic drug concentrations in the lungs, minimize systemic exposure, and consequently reduce the risk of systemic toxicity. A few inhalable nano-formulations are being developed for clinical trials (Table 2 ). Porous nano-formulations encapsulating docetaxel and celecoxib, fabricated via the emulsion-solvent evaporation method, exhibited significantly improved deposition efficiency in the lungs following particle size optimization. These findings indicate that this approach represents an effective and low-toxicity treatment option for lung tumors [ 186 ]. Fig. 13 Nano-formulations for treating pulmonary diseases Table 2 Inhalable nano-formulations under clinical application Drug Nanocarrier Indication Status Ref Amikacin Liposome Cystic Fibrosis patients with chronic pseudomonas aeruginosa infection Phase 3 NCT01316276 Amikacin Liposome Bronchiectasis Phase 2 NCT00775138 Salbutamol Sulphate Niosomes Pulmonary disease Phase 2 NCT03059017 Remdesivir (GS-5734) and NA-831 (NEUROSIVIR) Inhaled NP Severe acute respiratory syndrome Phase 1 NCT04480333 PRS-060 Lipocalin-1 Mild asthma Phase 1 NCT03574805

Nano-formulations: promising treatment in the therapy for cardiovascular diseases

Cardiovascular diseases (CVD) are the foremost cause of mortality worldwide, presenting significant threats to human health and life [ 187 ]. CVD encompasses a range of conditions including, but not limited to, atherosclerosis, hypertension, and myocardial infarction (MI), all of which can result in tissue ischemia and potentially fatal outcomes. Nano-formulations have shown great potential in repairing various organ injuries [ 188 ]. Nano-formulations are exhibiting substantial advantages and considerable potential in the diagnosis and treatment of CVD.

Application in molecular imaging

NPs exhibit a wide range of diagnostic applications in CVD, such as MRI, photoacoustic imaging, and computed tomography-positron emission tomography (CT-PET) imaging, among others [ 189 ]. As early as 1990, Weissleder et al . developed an ultra-small superparamagnetic iron oxide (USPIO) formulation for application in MRI [ 190 ]. Subsequently, biotin-modified liquid perfluorocarbon NPs, serving as a novel targeted ultrasound contrast agent, significantly enhanced the visualization of thrombosis [ 191 , 192 ]. Furthermore, hyaluronic acid-polypyrrole NPs loaded with doxorubicin have been developed for pH-responsive activatable fluorescence imaging, whereas AuNRs are employed for CT imaging [ 193 , 194 ].

Multimodal imaging signifies a significant advancement in the evolution of imaging technology. Nano-formulations are capable of efficiently integrating multiple imaging probes or contrast agents into a single system, thereby realizing a genuine multimodal imaging platform [ 195 , 196 ]. Utilizing tobacco mosaic virus (TMV) as a carrier, Michael et al. developed a targeted multimodal nano-contrast agent by incorporating near-infrared dye Cy5, chelated gadolinium (Gd) ions, and VCAM-1 peptides. This agent enables simultaneous magnetic resonance and fluorescence imaging of atherosclerotic plaques [ 197 ]. Kwon et al . developed thrombin-activated fluorescent peptides (TAP) incorporated into silica-coated AuNPs (TAP-SiO₂@AuNPs). This innovation enables the clear differentiation between thrombosis and surrounding tissues via dual-mode NIRF/micro-CT imaging in a mouse model [ 198 ].

Recently, Wu et al . developed a novel probe, CD40-Cy5.5-SPIONs, utilizing superparamagnetic iron oxide NPs (SPIONs) as the carrier to specifically target CD40 [ 199 ]. Upon intravenous administration into a mouse model of atherosclerosis, this probe demonstrated significant potential for MRI and optical dual-modality molecular imaging of vulnerable atherosclerotic plaques. In summary, the application of nano-formulations in molecular imaging has provided robust support for precise diagnosis and personalized medicine in cardiovascular diseases (Fig. 14 ). Fig. 14 Nano-formulations for molecular imaging

Atherosclerosis (AS)

Atherosclerosis (AS) is characterized by the deposition of blood components, such as lipids, within the arterial intima, accompanied by the proliferation of smooth muscle cells and an increase in collagen fibers. This process leads to the formation of lipid-rich, necrotic lesions with a porridge-like appearance. As the disease progresses, the hardening of the blood vessel walls may occur, and inflammation may develop in response to plaque formation [ 200 ]. Nano-formulations, leveraging their unique targeting delivery and high-efficiency therapeutic properties, exhibit significant advantages in the treatment of AS (Fig. 15 ). Fig. 15 Nano-formulations for the therapy of AS

Various forms of nanodrug carriers, including liposomes, nano-micelles, and inorganic NPs, can specifically target and deliver drugs to atherosclerotic plaque sites, thereby effectively prolonging the plasma half-life of the drugs [ 201 , 202 ]. The primary treatment methods encompass modulating lipoprotein levels, mitigating inflammation, reducing plaque area, and stabilizing vulnerable plaques [ 203 , 204 ].

Wu et al . investigated a specific type of PLGA NPs conjugated with EGFP-EGF1, which can be efficiently internalized by vascular smooth muscle cells (VSMCs) overexpressing tissue factor (TF) in vitro and effectively targeted to atherosclerotic plaques in vivo [ 205 ]. The surface of ENP is covalently functionalized with the EGFP-EGF1 protein, which specifically binds to tissue factor (TF), thereby conferring targeting capability to atherosclerotic plaques on the nanoparticles. PLGA is used as the polymer material, which has good biocompatibility and degradability, ensuring the safety of the drug delivery system. The nano-formulation facilitates the gradual release of the drug at the plaque site, thereby maintaining therapeutic concentrations effectively, reducing systemic exposure, and minimizing potential side effects. Zhao et al . developed a design approach for peptide-lipid NPs that mimics the functionality of HDL, thereby facilitating efficient cellular cholesterol efflux and leading to a significant reduction in plasma total cholesterol levels in mice with atherosclerosis [ 206 ]. Multiple peptide chains significantly enhance peptide-lipid affinity, improving the stability of nanoparticles and their cholesterol-binding capacity. By mimicking the function of ApoA-I protein in natural HDL, they facilitate cholesterol efflux to small, lipid-poor HDL particles, which constitutes a critical step in reverse cholesterol transport. The surface charge and hydrophilicity of the particles are optimized through the incorporation of cholesterol and PEGylated lipids, thereby prolonging their circulation time in vivo and preventing clearance by the phagocytic system.

Recently, Shin et al . developed an HDL-mimetic formulation that effectively displays multivalent ApoA-I peptides on the surfaces of protein nanotubes derived from TMV and virus-like particles sourced from bacteriophage Qβ. This formulation significantly enhances the efficiency of cholesterol efflux [ 207 ]. Mu et al . employed hyaluronic acid (HA)-coated poly(ethylene glycol)-poly(tyrosine ethyl oxalyl) (PEG-Ptyr-EO) biodegradable polymeric micelles for the encapsulation of simvastatin (SIM) [ 208 ]. The outer layer of HA specifically targeted inflammatory macrophages (CD44-positive), while the inner PEG-Ptyr-EO material was not only enzymatically degradable but also exhibited ROS responsiveness. This dual functionality allowed it to effectively consume ROS at the pathological site, thereby inhibiting the accumulation of proinflammatory macrophages and alleviating oxidative stress. Experiments demonstrated that this system could be effectively internalized by inflammatory cells and exhibits high cytotoxicity, while showing low toxicity to normal cells. In animal models, this system significantly reduced cholesterol levels in atherosclerotic plaques, exerting notable therapeutic effects. In another case, Xie et al . developed rod-shaped tubular micromotors by utilizing electrospun fiber segments as templates for the synthesis of polydopamine (PDA) microtubes [ 209 ]. These microtubes were loaded with urokinase plasminogen activator (uPA) and surface-modified with fucoidan (Fu), while simultaneously incorporating Escherichia coli Nissle 1917 (EcN) to develop hybrid micromotors. This approach not only extended the half-life of uPA and improved its bioavailability but also significantly enhanced thrombolytic capability, providing a promising therapeutic strategy for atherosclerosis.

MI

Clinically, growth factors, cytokines, and small molecule compounds are predominantly utilized for the treatment of myocardial ischemia. The ischemic regions of the myocardium demonstrate elevated vascular permeability, facilitating targeted delivery through the passive accumulation of nanodrug carriers. Additionally, the ischemic areas of the myocardium are frequently infiltrated by monocytes and macrophages, which can actively internalize nano-formulations for drug delivery via phagocytosis. Currently, nano-formulations have demonstrated revolutionary potential in the field of myocardial infarction treatment, with their precise drug delivery and efficient biological effects paving the way for novel approaches in myocardial protection and repair (Fig. 16 ). Fig. 16 Nano-formulations for the therapy of MI

Oxidative stress, characterized by excessive accumulation of reactive oxygen species (ROS), is associated with acute myocardial infarction (AMI) and the injury resulting from vascular reperfusion therapy. α-lipoic acid (α-LA) is a potent antioxidant; however, its therapeutic application is constrained by its rapid clearance and extensive distribution. Xie et al . utilized PLGA copolymer as a carrier to fabricate an electrospun LA@PLGA film, enabling the controlled release of LA to mitigate ROS-induced damage following myocardial injury and restore cardiac function [ 210 ]. Notoginsenoside R1 (NGR1), an active compound derived from Panax notoginseng, demonstrates therapeutic potential in the treatment of MI. Han et al . designed mesoporous silica NPs loaded with NGR1 and conjugated with CD11b antibodies (MSN-NGR1-CD11b), which are capable of specifically recognizing monocytes and neutrophils at the infarction site. In MI mice, intravenous administration of these NPs enhances cardiac function, stimulates angiogenesis, decreases apoptosis, and modulates macrophage polarization along with inflammatory cytokines and chemokines [ 211 ]. The receptor for advanced glycation endproducts (RAGE) has been implicated in a variety of chronic inflammatory conditions.

Lan et al . developed a ROS-degradable polycation, PPTP, specifically targeting myocardial inflammation resulting from ischemia/reperfusion (I/R) injury [ 212 ]. PPTP was utilized to functionalize mesoporous silica NPs (MSN) encapsulating dexamethasone (Dex), while simultaneously condensing RAGE small interfering RNA (siRAGE) and serving as a gatekeeper for MSN to prevent premature leakage of Dex. In a rat model of IR injury, the nanotherapeutic was efficiently delivered to inflamed cardiomyocytes via PGE2-mediated transport. The excessive ROS generated during IR injury degraded PPTP, leading to the controlled release of siRAGE and Dex, thereby achieving effective silencing of RAGE and a synergistic anti-inflammatory effect.

Other cardiovascular diseases

Significant advancements have been achieved in the research on nano-formulations for the treatment of various cardiovascular diseases, including hypertension, pulmonary arterial hypertension (PAH), and ischemic stroke. Currently, a wide range of antihypertensive drugs are available in clinical practice; however, these medications exhibit certain limitations, including low bioavailability and a short plasma half-life. In contrast, nano-formulations offer substantial advantages in these aspects. Telmisartan is an orally active, non-peptide angiotensin II receptor antagonist with relatively low water solubility, commonly utilized in the management of hypertension. Nevertheless, the utilization of telmisartan nanocrystals can significantly enhance oral bioavailability [ 213 ]. The curcumin nano-emulsion developed by Rachmawati et al . demonstrated a modest enhancement in its inhibitory effect on angiotensin-converting enzyme (ACE) [ 214 ]. Furthermore, regarding cholesterol reduction, the curcumin nano-emulsion demonstrates substantial efficacy, even outperforming the standard drug pravastatin.

PAH is a severe cardiopulmonary disorder characterized by the excessive proliferation and inflammation of pulmonary artery smooth muscle cells (PASMCs), for which effective therapeutic options remain limited [ 215 , 216 ]. Teng et al . co-delivered the apoptosis-executing gene p53 and the anti-inflammatory baicalein to PASMCs via a carrier-free method, with the objective of alleviating PAH [ 217 ]. The in vivo experiments demonstrated that this system specifically targets the lung-pulmonary artery-PASMC axis, thereby reducing pulmonary artery pressure, downregulating the pro-inflammatory cytokine TNF-α, and inhibiting pulmonary artery and right ventricular remodeling. Consequently, it effectively reverses monocrotaline-induced PAH. In another case, Vani et al . demonstrated that multi-hydroxy fullerene derivatives substantially reduced the area of brain injury in rats subjected to ischemic stroke, and significantly lowered the levels of malondialdehyde (MDA) and nitrate in the ischemic hemisphere [ 218 ]. Furthermore, the administration of fullerene NPs resulted in a significant increase in glutathione (GSH) content and superoxide dismutase (SOD) activity. This enhancement effectively mitigated the elevated levels of free radicals under ischemic conditions, thereby providing robust protection against ischemic/reperfusion injury to brain cells.

It can thus be seen that nano-formulations will one day also become a powerful tool for the diagnosis and treatment of cardiovascular diseases (Fig. 17 ). Fig. 17 Nano-formulations in the therapy for cardiovascular diseases

Nano-formulation applications in treating diabetes

Diabetes has emerged as one of the prevalent metabolic diseases globally, characterized by inadequate insulin secretion and/or action, leading to hyperglycemia [ 219 , 220 ]. Anti-diabetic nano-formulations represent a significant advancement in the field of diabetes treatment, capable of reducing enzymatic degradation of specific anti-diabetic drugs, such as insulin, within the gastrointestinal (GI) tract. This enhancement improves drug delivery efficiency and therapeutic efficacy [ 221 , 222 ]. Nano-formulations exhibit multifaceted application potential in diabetes therapy, as illustrated in Fig. 18 . Fig. 18 Schematic model of nano-formulations in treating diabetes. A Schematic illustration of the action of insulin-loaded and H 2 O 2 -responsive mesoporous silica nanoparticles (MSNs). B Schematic illustration of the action of Amentoflavone-loaded P (NVP-MGAM)/AF oral microspheres Adapted from Xu B, Jiang G, Yu W, et al . H 2 O 2 -Responsive mesoporous silica nanoparticles integrated with microneedle patches for the glucose-monitored transdermal delivery of insulin. J Mater Chem B. 2017;5(41):8200–8. Zhang J, Zhou J, Zhang T, et al . Facile Fabrication of an Amentoflavone-Loaded Micelle System for Oral Delivery To Improve Bioavailability and Hypoglycemic Effects in KKAy Mice. ACS Applied Materials & Interfaces. 2019;11(13):12,904–13

Hunt et al . have developed a novel oral insulin nano-formulation consisting of insulin-conjugated silver sulfide quantum dots coated with chitosan/glucose polymers [ 223 ]. This formulation remains insoluble in acidic environments but demonstrates significantly enhanced absorption at neutral pH levels, such as those observed in the human duodenum. Additionally, it is sensitive to glucosidase, which triggers insulin release. Experiments have demonstrated that this formulation significantly reduces blood glucose levels in mice, rats, and non-diabetic baboons, with no observed adverse effects such as hypoglycemia, weight gain, or hematological toxicity. Xu et al . have designed a novel microneedle (MN) delivery device integrated with insulin-loaded and H 2 O 2 -responsive MSNs [ 224 ]. These MSNs, synthesized via targeted modification and host–guest complexation, exhibit a glucose-responsive behavior. Upon the conversion of glucose to gluconic acid and the concurrent generation of hydrogen peroxide, the chemical bonds on the MSN surface undergo oxidative cleavage, resulting in NP disintegration and subsequent insulin release. In experiments conducted on diabetic rats, this device exhibited significant hypoglycemic efficacy following percutaneous administration, as compared to subcutaneous injection.

Shrestha et al . have developed a nanosystem capable of simultaneously delivering glucagon-like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP4) inhibitors [ 225 ]. The system, which employs chitosan-modified porous silicon nanoparticles as the core, simultaneously encapsulates GLP-1 and DPP4 inhibitors to achieve a synergistic effect, thereby enhancing insulin secretion and inhibiting GLP-1 degradation. The intestinal polymer coating serves as a protective barrier against acid-induced and enzymatic degradation, thereby safeguarding the drugs from the adverse effects of the harsh gastrointestinal environment. Oral administration of this nano-system significantly reduced blood glucose levels and increases pancreatic insulin content. Polyphenols, as secondary metabolites in plants, exhibit potential antidiabetic properties [ 226 ]. Zhang et al . pioneered the development of the P(NVP-MGAM)/AF oral micellar system, which markedly enhanced the oral bioavailability of hop flavonoids [ 227 ]. In a mouse model of diabetes characterized by insulin resistance, this micellar system exhibited significant therapeutic efficacy via mechanisms including the regulation of blood lipids, attenuation of inflammation, and activation of PPARγ as well as the PI3K/Akt signaling pathways.

Opportunities for nano-formulations in treating skin disease

Skin conditions represent one of the most widespread health concerns, imposing considerable economic and psychological burdens on affected individuals. Owing to the barrier function of the skin and the unfavorable physicochemical properties of certain drugs, transdermal drug delivery poses a considerable challenge [ 228 ]. Skin conditions can primarily be categorized into two groups: barrier-impaired skin conditions, which include atopic dermatitis, psoriasis, and fungal infections; and follicular disorders, which encompass acne and alopecia [ 229 ]. Barrier-impaired skin diseases predominantly affect the active epidermal cell layer and the dermis, whereas targeting hair follicles is essential for the effective treatment of follicular skin conditions. Advancements and innovations in drug delivery systems, especially with the emergence of nano-formulations, have facilitated significant breakthroughs in the treatment of dermatological conditions [ 230 ].

Tacrolimus (TRL), an immunosuppressive agent utilized in the management of atopic dermatitis (AD), demonstrates efficacy; however, its clinical application is constrained by its poor water solubility, low permeability, and potential cytotoxicity. To address these challenges, Ren et al . innovatively developed a novel formulation by embedding tacrolimus-loaded nano-transfersomes (TRL-NTs) into chitosan gel, thereby forming the TRL-NTs gel (TRL-NTsG) [ 231 ]. TRL-NTsG not only demonstrates markedly superior efficiency in the release of tacrolimus compared to traditional formulations, but also achieves substantial improvements in permeability and stability. In an animal model of AD, mice treated with TRL-NTsG exhibited a significant reduction in ear thickness. Furthermore, these mice showed a notable decrease in IgE levels, suggesting that TRL-NTsG may effectively mitigate AD-associated immune responses. In another study, Fratoddi et al . modified AuNPs using 3-mercapto-1-propanesulfonic acid salt, resulting in AuNPs-3MPS, which were subsequently loaded with the immunosuppressant methotrexate (MTX) [ 232 ]. AUNPS-3MP confers novel chemical and physical properties on AuNPs, such as an enhanced drug-loading capacity, improved stability, and increased targeting ability. The AUNPS-3MP coating effectively mitigates the degradation of MTX during delivery, thereby preserving its immunosuppressive activity. AuNPs inherently exhibit excellent biocompatibility and degradability. Furthermore, after modification with AUNPS-3MP, their immunogenicity is significantly diminished, making them highly suitable for long-term administration. The resultant AuNPs-3MPS@MTX formulation significantly mitigated scales, erythema, epidermal thickness, and inflammatory infiltration in a murine model of psoriasis. Furthermore, the solid lipid NPs loaded with fluconazole (FLZ-SLN) developed by Moazeni et al . have also shown efficacy against strains exhibiting reduced sensitivity to conventional fluconazole formulations [ 233 ]. The alterations in the microenvironment of hair follicles caused by acne, including an elevation in pH levels, have prompted innovative therapeutic approaches.

Dong et al . developed pH-sensitive polyacrylic resin I (Eudragit ® L-100) NPs encapsulating spin-labeled dexamethasone (DxPCA) [ 234 ]. The findings demonstrated that DxPCA-Eudragit ® L-100 NPs exhibited markedly enhanced skin penetration and drug release properties, facilitating targeted delivery to hair follicles for the treatment of dermatological conditions such as acne. Minoxidil serves as an efficacious topical therapy for hair loss; however, it is constrained by a slow onset of action and limited efficacy. Moreover, it lacks the capability to effectively mitigate excessive oxidative stress, a significant pathogenic factor contributing to hair loss. Xiao et al . leveraged the transition metal molybdenum, known for its rapid electron transfer properties, to mitigate oxidative stress [ 235 ]. They conducted an intervention study on a mouse hair growth model using nano-molybdenum, minoxidil, and a combination of both treatments. The findings indicated that nano-molybdenum not only accelerated hair growth and increased the number of hair follicles but also reduced the expression levels of molecules associated with oxidative stress. Furthermore, when combined with minoxidil, nano-molybdenum exhibited a synergistic effect in promoting hair growth. In summary, nano-formulations have demonstrated immense potential and a broad application prospect in the field of skin disease treatment (Fig. 19 ). Fig. 19 Nano-formulations in treating skin disease

Potential role of nano-formulations in treating eye diseases

Eye diseases exert a significant impact on both the visual function and overall quality of life for patients globally [ 236 ]. Nevertheless, the unique and intricate anatomical and physiological features of the eye present substantial challenges for achieving effective ocular drug delivery within the realms of clinical pharmacology and biomaterials science [ 237 ]. To address these challenges, nano-formulations for ophthalmic use with precise delivery characteristics have emerged [ 238 ]. Researchers have developed a range of innovative nanotechnology-based drug delivery systems designed to extend drug residence time in the eye and enhance corneal permeability, thereby improving the bioavailability of drugs within ocular tissues (Fig. 20 ). Fig. 20 Nano-formulations in treating ocular diseases

Dry eye disease (DED) is progressively impacting an increasingly large global population, with its etiology encompassing ocular surface inflammation and oxidative stress [ 239 ]. Cui et al . have developed a nanoceramic material loaded with cyclosporine A (Cs@P/CeO 2 ), which exhibits prolonged antioxidant and anti-inflammatory properties due to its regenerative antioxidant activity and sustained release of cyclosporine A [ 240 ]. Their findings indicated that Cs@P/CeO 2 could restore the balance of immune-epithelial communication in the corneal microenvironment, reduce the polarization of inflammatory macrophages, and mitigate oxidative stress. Nano-ceria exhibits self-regenerative antioxidant capacity, which stems from the reversible switching between Ce 3 ⁺ and Ce 4 ⁺ ions due to oxygen vacancies. Simultaneously, it is loaded with the immunomodulatory agent Cyclosporin A, thereby achieving dual functionalities of antioxidant defense and immunomodulatory effects. The eye drops are modified with PEG to enhance the biocompatibility and hydrophilicity of nano-ceria, and to enable slow-release of cyclosporine A, thereby prolonging the ocular surface residence time and providing long-term antioxidant and anti-inflammatory effects.

Glaucoma is a progressive and irreversible ocular disorder characterized by the degeneration and loss of retinal ganglion cells (RGCs) [ 241 ]. Zhou et al . have developed a dual-drug conjugate (OLN monomer) that is responsive to ROS [ 242 ]. This conjugate, which integrates nicotinamide and oleic acid, can self-assemble into NPs (uhOLN-NPs) with ROS scavenging capabilities. Subsequently, the researchers encapsulated these uhOLN-NPs using a hypoxia-responsive polymer, resulting in NPs (HOLN-NPs) that exhibit responsiveness to both hypoxia and ROS. When RGCs are subjected to hypoxic conditions or elevated ROS levels, HOLN-NPs release uhOLN-NPs, which subsequently release nicotinamide and oleic acid. These compounds not only effectively scavenge ROS but also activate the CaMKII/CREB signaling pathway, thereby providing protection for mitochondrial function in RGCs. The utilization of contact lenses as a vehicle for ocular drug delivery is regarded as a promising alternative to traditional eyedrops. However, this approach encounters challenges including suboptimal drug uptake efficiency, lens hydration-induced swelling, and diminished optical transmittance [ 243 ].

2D materials can also be utilized for treating eye diseases. For instance, Maulvi et al . incorporated graphene oxide (GO) into silicone hydrogel contact lenses [ 244 ]. These lenses were either immersed in a bimatoprost solution or fabricated with bimatoprost directly incorporated during the lens polymerization process, resulting in contact lenses with or without GO. The incorporation of GO into the contact lenses effectively regulated the release of bimatoprost, while enhancing the lens's swelling behavior and optical transmittance properties. Compared to the administration of eyedrops, the use of contact lenses containing GO and an appropriate concentration of bimatoprost markedly increased the mean residence time (MRT) and area under the curve (AUC) of the drug.

Challenges and prospects

Nano-formulations, resulting from the integration of cutting-edge technology and medical expertise, are quietly spearheading a transformative shift in the medical field. They function as precise “drug delivery vehicles”, capable of directly administering therapeutic agents to specific cells or tissues within the human body. This approach not only significantly enhances drug efficacy but also markedly reduces adverse effects, thereby realizing the true potential of targeted therapy. In the field of drug delivery, nano-formulations exhibit unparalleled advantages. They are capable of efficiently traversing biological barriers and accurately delivering drugs to the site of lesions, be it malignant tumors, chronic pulmonary conditions, complex cardiovascular diseases, or refractory conditions such as diabetes, fragile ocular diseases, and recalcitrant dermatological disorders, thereby enabling more precise and effective therapeutic interventions. Furthermore, nano-formulations are capable of achieving stable drug release within the body, thereby maintaining therapeutic concentrations and prolonging treatment duration, which ultimately enhances therapeutic efficacy. In the realm of diagnostics and imaging, the utilization of nanoprobes is equally significant. They can interact with specific cells or molecules, thereby providing more precise and sensitive information for disease diagnosis. Leveraging advanced imaging technologies, physicians can clearly visualize changes at the lesion site, offering robust support for early detection and treatment of diseases.

Nevertheless, the application of nano-formulations faces several challenges. Potential toxicity and biocompatibility concerns have consistently posed significant challenges that impede their advancement. Ensuring the safety and stability of nano-formulations within biological systems while preventing potential damage to healthy tissues remains a critical challenge that researchers must urgently address. Furthermore, the limitations encountered during the delivery process of NPs pose significant challenges to their clinical translation. Currently, there is a significant gap in our comprehensive understanding of the disposition and metabolic pathways of nanodrugs within the human body, thereby heightening the risks and uncertainties inherent in drug development. Regarding quality control, nano-formulations also encounter substantial challenges. Parameters such as diameter, size distribution, morphology, surface charge, drug loading capacity, and release profile are directly correlated with the stability and efficacy of nano-formulations. Consequently, the establishment of a more rigorous and precise quality control system to ensure that each batch of nano-formulations achieves optimal therapeutic outcomes represents a significant challenge that researchers must address.

Despite encountering numerous challenges, the prospects for the development of nano-formulations remain promising. It is imperative to conduct in-depth research into critical areas such as the mechanisms of toxicity associated with nano-formulations, strategies to enhance biocompatibility, optimization methods for delivery systems, and advancements in quality control technologies. Currently, advanced materials, coatings, or surface modifications are being developed to enhance biocompatibility. For instance, biodegradable materials including PLGA, chitosan, liposome and other detachable carrier (e.g. hydrolysis of silicon-based nanoparticles to silicic acid), have be1en used to reduce long-term toxicity. Surface modification using by Pegs (pegylation) or coating with hydrophilic polymers (e.g., polyvinylpyrrolidone, PVP) can reduce immunogenicity and avoid clearance of the RES [ 245 ]. pH, enzyme, or REDOX responsive nano-formulations can be designed to release drugs in specific microenvironments (such as low pH or high glutathione environments). Furthermore, surface engineering strategies, including charge regulation and bionic design utilizing exosomes or lipoprotein-mimic nanoparticles, have been developed to enhance biocompatibility. The "optical switch nanocarriers" developed by Stanford University enable precise control over the timing of release through varying wavelengths of light [ 246 ]. Additionally, selenide nanoparticles have emerged as a research focus owing to their enhanced redox sensitivity. In addition, AI facilitates the acceleration of nanomaterial screening, drug carrier optimization, and clinical trial design by enhancing computational efficiency and data analysis capabilities. Generative AI models, such as Google DeepMind's Material Exploration Network, predict thousands of stable nanostructures. AI-designed peptide nanotubes have the ability to self-assemble into scaffolds for drug delivery (for Alzheimer's disease) [ 247 ]. Optimization of drug delivery using AI technology especially the machine learning can predict release dynamics. The MIT team employed neural networks to optimize the polymer composition of nanoparticles, thereby reducing the drug release time error to less than 5% [ 248 ]. NVIDIA's Clara platform simulates the distribution of nano-formulation within the human body, thereby minimizing the reliance on animal testing. Deep learning integrated with AI-based screening for targeted ligands is employed to analyze tumor cell surface proteome data and design specific peptide sequences, such as nanoparticles targeting PD-L1. We look forward to the emergence of more innovative nano-formulations that will not only improve treatment outcomes but also enhance the quality of life for patients.

Conclusions

By precisely controlling drug delivery and release, nano-formulations not only significantly improve therapeutic effects but also reduce the side effects associated with traditional treatments, offering new possibilities for the treatment of multiple diseases. Although challenges such as toxicity, biocompatibility, delivery efficiency, and quality control arise in practical applications, these issues are gradually being addressed through continuous scientific research and technological advancements. In the future, nano-formulations are expected to play a pivotal role in the treatment of more diseases, further enhancing medical standards, improving patients' quality of life, and bringing revolutionary changes to the field of medicine.

In summary, we presented a comprehensive review on the design and synthesis of nano-formulations, action mechanisms, applications in molecular imaging, and the treatment of various diseases. In particular, we systematically elucidate the application of novel nano-formulations in disease diagnosis and treatment, while critically analyzing the difficulties and challenges encountered during implementation. Despite being rigorously validated through extensive research, such detailed and comprehensive studies remain underreported in the existing literature.

Abbreviations

Metastatic breast cancer

Pancreatic cancer

Non-small cell lung cancer

Ovarian cancer

Therapy-related acute myeloid leukemia

AML with myelodysplasia-related changes

Small interfering RNA

Acquired thrombotic thrombocytopenic purpura

Messenger RNA

Nanoparticles

Polylactic acid

Polyglycolic acid

Natural killer

Biomimetic nanoparticles

Enhanced permeability and retention

Nanodiscs

High-density lipoproteins

Scavenger Receptor Class B Type 1

Folate receptors

Low-density lipoprotein

Fluorescence imaging

Magnetic resonance imaging

Computed tomography

Positron emission tomography

Pegylated liposomes

Arg-Gly-Asp

Near-infrared

Magnetic nanoparticles

Reactive oxygen species

Cancer cell membrane-coated nanoparticles

Indocyanine green

Fluorescence/photoacoustic

Epithelial-to-Mesenchymal Transition

Withaferin-A

Gold nanoparticles

ATP-binding cassette subfamily G member 2

Dendritic nanoparticles

Programmed cell death ligand 1

Docetaxel

Borate cross-linked micelle

Paclitaxel

Non-cross-linked micelles

Hydroxypropyl methacrylamide

Heat shock protein 90

Reticuloendothelial system

Adoptive cell therapy

Monoclonal antibody

Progression-free survival

Overall survival

Immune checkpoint inhibitors

Programmed cell death protein 1

Hodgkin lymphoma

Cytotoxic T-lymphocyte-associated protein 4

Colorectal cancer

Protein hydrolysis-targeting chimeras

Protein of interest

PH/cathepsin B sequentially responsive nanoparticles

Cyclin-dependent kinases 4 and 6

Colorectal cancer

Immune checkpoint blockades

Chimeric antigen receptor T cell immunotherapy

Chimeric antigen receptors

Nanogels

T-cell receptor

Epidermal growth factor receptor

Prostate-specific membrane antigen

Human epidermal growth factor receptor 2

Antibody–drug conjugates

Trastuzumab

Antigen-presenting cells

Dendritic cell

Anti-PD-L1 antibody

Cytotoxic T lymphocytes

Lipid nanoparticles

Tumor microenvironment

Tropomyosin receptor kinase

Tumor-associated macrophages

Outer membrane vesicles

Messenger RNA

Phenylboronic acid

Sialic acid

Doxorubicin

Milk-derived exosomes

Photodynamic Therapy

Photothermal Therapy

Gold nanorods

Polo-like kinase-1

Multidrug resistance

ATP-binding cassette

Chronic obstructive pulmonary disease

Cardiovascular diseases

Myocardial infarction

Computed tomography-positron emission tomography

Ultra-small superparamagnetic iron oxide

Tobacco mosaic virus

Thrombin-activated fluorescent peptides

Superparamagnetic iron oxide nanoparticles

Atherosclerosis

Vascular smooth muscle cells

Tissue factor

Hyaluronic acid

Simvastatin

Polydopamine

Urokinase plasminogen activator

Fucoidan

Acute myocardial infarction

α-Lipoic acid

Notoginsenoside R1

Receptor for advanced glycation endproducts

Ischemia/reperfusion

Mesoporous silica nanoparticles

Dexamethasone

Pulmonary arterial hypertension

Angiotensin-converting enzyme

Pulmonary artery smooth muscle cells

Malondialdehyde

Glutathione

Superoxide dismutase

Gastrointestinal

Microneedle

Glucagon-like peptide-1

Dipeptidyl peptidase-4

Tacrolimus

Atopic dermatitis

Methotrexate

Dry eye disease

Retinal ganglion cells

Graphene oxide

Mean residence time

Area under the curve

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

The authors would like to thank Figdraw for the assistance in creating the scheme.

Author contributions

YunYan Shi and Gang Wei: Writing-original draft, Conceptualization, Data curation, Investigation. YunYan Shi: Writing-original draft, Visualization. Xiao Li: Writing-original draft. Zhiyuan Li: Visualization. Xiao Li, Zhiyuan Li, Jialin Sun and Tong Gao: Data curation. Qie Guo and Gang Wei: Writing-review & editing, Conceptualization, Funding acquisition, Supervision, Validation. All authors read and approved the final manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (82204433) and Taishan Scholars Program of Shandong Province (tsqn201909104).

Availability of data and materials

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

References

1. Jeevanandam J Chan YS Danquah MK Nano-formulations of drugs: recent developments, impact and challenges Biochimie 2016 128–129 99 112 10.1016/j.biochi.2016.07.008 27436182 Jeevanandam J, Chan YS, Danquah MK. Nano-formulations of drugs: recent developments, impact and challenges. Biochimie. 2016;128–129:99–112. 27436182 10.1016/j.biochi.2016.07.008

2. Soppimath KS Aminabhavi TM Kulkarni AR Biodegradable polymeric nanoparticles as drug delivery devices J Control Release 2001 70 1–2 1 20 10.1016/S0168-3659(00)00339-4 11166403 Soppimath KS, Aminabhavi TM, Kulkarni AR, et al. Biodegradable polymeric nanoparticles as drug delivery devices. J Control Release. 2001;70(1–2):1–20. 11166403 10.1016/s0168-3659(00)00339-4

3. Erdoğar N Akkın S Bilensoy E Nanocapsules for drug delivery: an updated review of the last decade Recent Pat Drug Deliv Formul 2018 12 4 252 266 10.2174/1872211313666190123153711 30674269 Erdoğar N, Akkın S, Bilensoy E. Nanocapsules for drug delivery: an updated review of the last decade. Recent Pat Drug Deliv Formul. 2018;12(4):252–66. 30674269 10.2174/1872211313666190123153711

4. Miguel RDA Hirata AS Jimenez PC Beyond formulation: contributions of nanotechnology for translation of anticancer natural products into new drugs Pharmaceutics 2022 14 8 1772 10.3390/pharmaceutics14081722 36015347 PMC9415580 Miguel RDA, Hirata AS, Jimenez PC, et al. Beyond formulation: contributions of nanotechnology for translation of anticancer natural products into new drugs. Pharmaceutics. 2022;14(8):1772. 36015347 10.3390/pharmaceutics14081722 PMC9415580

5. Gregoriadis G Ryman BE Liposomes as carriers of enzymes or drugs: a new approach to the treatment of storage diseases Biochem J 1971 124 5 58p 10.1042/bj1240058P 5130994 PMC1177319 Gregoriadis G, Ryman BE. Liposomes as carriers of enzymes or drugs: a new approach to the treatment of storage diseases. Biochem J. 1971;124(5):58p. 5130994 10.1042/bj1240058p PMC1177319

6. Stone NR Bicanic T Salim R Liposomal amphotericin B (AmBisome(®)): a review of the pharmacokinetics, pharmacodynamics, clinical experience and future directions Drugs 2016 76 4 485 500 10.1007/s40265-016-0538-7 26818726 PMC4856207 Stone NR, Bicanic T, Salim R, et al. Liposomal amphotericin B (AmBisome(®)): a review of the pharmacokinetics, pharmacodynamics, clinical experience and future directions. Drugs. 2016;76(4):485–500. 26818726 10.1007/s40265-016-0538-7 PMC4856207

7. Porche DJ Liposomal doxorubicin (Doxil) J Assoc Nurses AIDS Care 1996 7 2 55 59 10.1016/S1055-3290(96)80016-1 8679968 Porche DJ. Liposomal doxorubicin (Doxil). J Assoc Nurses AIDS Care. 1996;7(2):55–9. 8679968 10.1016/S1055-3290(96)80016-1

8. Gradishar WJ Tjulandin S Davidson N Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer J Clin Oncol 2005 23 31 7794 7803 10.1200/JCO.2005.04.937 16172456 Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23(31):7794–803. 16172456 10.1200/JCO.2005.04.937

9. Lee KS Chung HC Im SA Multicenter phase II trial of genexol-PM, a cremophor-free, polymeric micelle formulation of paclitaxel, in patients with metastatic breast cancer Breast Cancer Res Treat 2008 108 2 241 250 10.1007/s10549-007-9591-y 17476588 Lee KS, Chung HC, Im SA, et al. Multicenter phase II trial of genexol-PM, a cremophor-free, polymeric micelle formulation of paclitaxel, in patients with metastatic breast cancer. Breast Cancer Res Treat. 2008;108(2):241–50. 17476588 10.1007/s10549-007-9591-y

10. Alfayez M Kantarjian H Kadia T CPX-351 (vyxeos) in AML Leuk Lymphoma 2020 61 2 288 297 10.1080/10428194.2019.1660970 31547736 Alfayez M, Kantarjian H, Kadia T, et al. CPX-351 (vyxeos) in AML. Leuk Lymphoma. 2020;61(2):288–97. 31547736 10.1080/10428194.2019.1660970

11. Hoy SM Patisiran: first global approval Drugs 2018 78 15 1625 1631 10.1007/s40265-018-0983-6 30251172 Hoy SM. Patisiran: first global approval. Drugs. 2018;78(15):1625–31. 30251172 10.1007/s40265-018-0983-6

12. Duggan S Caplacizumab: first global approval Drugs 2018 78 15 1639 1642 10.1007/s40265-018-0989-0 30298461 PMC6280848 Duggan S. Caplacizumab: first global approval. Drugs. 2018;78(15):1639–42. 30298461 10.1007/s40265-018-0989-0 PMC6280848

13. Teo SP Review of COVID-19 mRNA vaccines: BNT162b2 and mRNA-1273 J Pharm Pract 2022 35 6 947 951 10.1177/08971900211009650 33840294 Teo SP. Review of COVID-19 mRNA vaccines: BNT162b2 and mRNA-1273. J Pharm Pract. 2022;35(6):947–51. 33840294 10.1177/08971900211009650

14. Hargreaves R Ferreira JC Hughes D Development of aprepitant, the first neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting Ann NY Acad Sci 2011 1222 40 48 10.1111/j.1749-6632.2011.05961.x 21434941 Hargreaves R, Ferreira JC, Hughes D, et al. Development of aprepitant, the first neurokinin-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting. Ann NY Acad Sci. 2011;1222:40–8. 21434941 10.1111/j.1749-6632.2011.05961.x

15. Khan O Chaudary N The use of Amikacin liposome inhalation suspension (Arikayce) in the treatment of refractory nontuberculous mycobacterial lung disease in adults Drug Des Devel Ther 2020 14 2287 2294 10.2147/DDDT.S146111 32606598 PMC7293904 Khan O, Chaudary N. The use of Amikacin liposome inhalation suspension (Arikayce) in the treatment of refractory nontuberculous mycobacterial lung disease in adults. Drug Des Devel Ther. 2020;14:2287–94. 32606598 10.2147/DDDT.S146111 PMC7293904

16. Dean AQ Luo S Twomey JD Targeting cancer with antibody-drug conjugates: promises and challenges MAbs 2021 13 1 1951427 10.1080/19420862.2021.1951427 34291723 PMC8300931 Dean AQ, Luo S, Twomey JD, et al. Targeting cancer with antibody-drug conjugates: promises and challenges. MAbs. 2021;13(1):1951427. 34291723 10.1080/19420862.2021.1951427 PMC8300931

17. Nelemans LC Gurevich L Drug delivery with polymeric nanocarriers-cellular uptake mechanisms Materials 2020 13 2 1 10.3390/ma13020366 PMC7013754 31941006 Nelemans LC, Gurevich L. Drug delivery with polymeric nanocarriers-cellular uptake mechanisms. Materials. 2020;13(2):1. 10.3390/ma13020366 PMC7013754 31941006

18. Alqosaibi AI Nanocarriers for anticancer drugs: challenges and perspectives Saudi J Biol Sci 2022 29 6 103298 10.1016/j.sjbs.2022.103298 35645591 PMC9130109 Alqosaibi AI. Nanocarriers for anticancer drugs: challenges and perspectives. Saudi J Biol Sci. 2022;29(6): 103298. 35645591 10.1016/j.sjbs.2022.103298 PMC9130109

19. Ghanbari-Movahed M Kaceli T Mondal A Recent advances in improved anticancer efficacies of camptothecin nano-formulations: a systematic review Biomedicines 2021 9 5 1 10.3390/biomedicines9050480 PMC8146681 33925750 Ghanbari-Movahed M, Kaceli T, Mondal A, et al. Recent advances in improved anticancer efficacies of camptothecin nano-formulations: a systematic review. Biomedicines. 2021;9(5):1. 10.3390/biomedicines9050480 PMC8146681 33925750

20. Kubik T Bogunia-Kubik K Sugisaka M Nanotechnology on duty in medical applications Curr Pharm Biotechnol 2005 6 1 17 33 10.2174/1389201053167248 15727553 Kubik T, Bogunia-Kubik K, Sugisaka M. Nanotechnology on duty in medical applications. Curr Pharm Biotechnol. 2005;6(1):17–33. 15727553 10.2174/1389201053167248

21. Sinha R Kim GJ Nie S Nanotechnology in cancer therapeutics: bioconjugated nanoparticles for drug delivery Mol Cancer Ther 2006 5 8 1909 1917 10.1158/1535-7163.MCT-06-0141 16928810 Sinha R, Kim GJ, Nie S, et al. Nanotechnology in cancer therapeutics: bioconjugated nanoparticles for drug delivery. Mol Cancer Ther. 2006;5(8):1909–17. 16928810 10.1158/1535-7163.MCT-06-0141

22. Elzoghby AO Abdelmoneem MA Hassanin IA Lactoferrin, a multi-functional glycoprotein: active therapeutic, drug nanocarrier & targeting ligand Biomaterials 2020 263 120355 10.1016/j.biomaterials.2020.120355 32932142 PMC7480805 Elzoghby AO, Abdelmoneem MA, Hassanin IA, et al. Lactoferrin, a multi-functional glycoprotein: active therapeutic, drug nanocarrier & targeting ligand. Biomaterials. 2020;263: 120355. 32932142 10.1016/j.biomaterials.2020.120355 PMC7480805

23. Miao D Jiang M Liu Z Co-administration of dual-targeting nanoparticles with penetration enhancement peptide for antiglioblastoma therapy Mol Pharm 2014 11 1 90 101 10.1021/mp400189j 24295590 Miao D, Jiang M, Liu Z, et al. Co-administration of dual-targeting nanoparticles with penetration enhancement peptide for antiglioblastoma therapy. Mol Pharm. 2014;11(1):90–101. 24295590 10.1021/mp400189j

24. Godlewska M Majkowska-Pilip A Stachurska A Voltammetric and biological studies of folate-targeted non-lamellar lipid mesophases Electrochim Acta 2019 299 1 11 10.1016/j.electacta.2018.12.164 Godlewska M, Majkowska-Pilip A, Stachurska A, et al. Voltammetric and biological studies of folate-targeted non-lamellar lipid mesophases. Electrochim Acta. 2019;299:1–11.

25. Wei D Sun Y Zhu H Stimuli-responsive polymer-based nanosystems for cancer theranostics ACS Nano 2023 17 23 23223 23261 10.1021/acsnano.3c06019 38041800 Wei D, Sun Y, Zhu H, et al. Stimuli-responsive polymer-based nanosystems for cancer theranostics. ACS Nano. 2023;17(23):23223–61. 38041800 10.1021/acsnano.3c06019

26. Lin X Song X Zhang Y Multifunctional theranostic nanosystems enabling photothermal-chemo combination therapy of triple-stimuli-responsive drug release with magnetic resonance imaging Biomater Sci 2020 8 7 1875 1884 10.1039/C9BM01482A 32010912 Lin X, Song X, Zhang Y, et al. Multifunctional theranostic nanosystems enabling photothermal-chemo combination therapy of triple-stimuli-responsive drug release with magnetic resonance imaging. Biomater Sci. 2020;8(7):1875–84. 32010912 10.1039/c9bm01482a

27. Chen L Hong W Ren W Recent progress in targeted delivery vectors based on biomimetic nanoparticles Signal Transduct Target Ther 2021 6 1 225 10.1038/s41392-021-00631-2 34099630 PMC8182741 Chen L, Hong W, Ren W, et al. Recent progress in targeted delivery vectors based on biomimetic nanoparticles. Signal Transduct Target Ther. 2021;6(1):225. 34099630 10.1038/s41392-021-00631-2 PMC8182741

28. Fang RH Kroll AV Gao W Cell membrane coating nanotechnology Adv Mater 2018 30 23 e1706759 10.1002/adma.201706759 29582476 PMC5984176 Fang RH, Kroll AV, Gao W, et al. Cell membrane coating nanotechnology. Adv Mater. 2018;30(23): e1706759. 29582476 10.1002/adma.201706759 PMC5984176

29. Han X Shen S Fan Q Red blood cell-derived nanoerythrosome for antigen delivery with enhanced cancer immunotherapy Sci Adv 2019 5 10 eaaw6870 10.1126/sciadv.aaw6870 31681841 PMC6810293 Han X, Shen S, Fan Q, et al. Red blood cell-derived nanoerythrosome for antigen delivery with enhanced cancer immunotherapy. Sci Adv. 2019;5(10):eaaw6870. 31681841 10.1126/sciadv.aaw6870 PMC6810293

30. Parodi A Quattrocchi N van de Ven AL Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions Nat Nanotechnol 2013 8 1 61 68 10.1038/nnano.2012.212 23241654 PMC3751189 Parodi A, Quattrocchi N, van de Ven AL, et al. Synthetic nanoparticles functionalized with biomimetic leukocyte membranes possess cell-like functions. Nat Nanotechnol. 2013;8(1):61–8. 23241654 10.1038/nnano.2012.212 PMC3751189

31. Chen Z Zhao P Luo Z Cancer cell membrane-biomimetic nanoparticles for homologous-targeting dual-modal imaging and photothermal therapy ACS Nano 2016 10 11 10049 10057 10.1021/acsnano.6b04695 27934074 Chen Z, Zhao P, Luo Z, et al. Cancer cell membrane-biomimetic nanoparticles for homologous-targeting dual-modal imaging and photothermal therapy. ACS Nano. 2016;10(11):10049–57. 27934074 10.1021/acsnano.6b04695

32. Xiong J Wu M Chen J Cancer-erythrocyte hybrid membrane-camouflaged magnetic nanoparticles with enhanced photothermal-immunotherapy for ovarian cancer ACS Nano 2021 15 12 19756 19770 10.1021/acsnano.1c07180 34860006 Xiong J, Wu M, Chen J, et al. Cancer-erythrocyte hybrid membrane-camouflaged magnetic nanoparticles with enhanced photothermal-immunotherapy for ovarian cancer. ACS Nano. 2021;15(12):19756–70. 34860006 10.1021/acsnano.1c07180

33. Kao CY Papoutsakis ET Extracellular vesicles: exosomes, microparticles, their parts, and their targets to enable their biomanufacturing and clinical applications Curr Opin Biotechnol 2019 60 89 98 10.1016/j.copbio.2019.01.005 30851486 Kao CY, Papoutsakis ET. Extracellular vesicles: exosomes, microparticles, their parts, and their targets to enable their biomanufacturing and clinical applications. Curr Opin Biotechnol. 2019;60:89–98. 30851486 10.1016/j.copbio.2019.01.005

34. Chung YH Cai H Steinmetz NF Viral nanoparticles for drug delivery, imaging, immunotherapy, and theranostic applications Adv Drug Deliv Rev 2020 156 214 235 10.1016/j.addr.2020.06.024 32603813 PMC7320870 Chung YH, Cai H, Steinmetz NF. Viral nanoparticles for drug delivery, imaging, immunotherapy, and theranostic applications. Adv Drug Deliv Rev. 2020;156:214–35. 32603813 10.1016/j.addr.2020.06.024 PMC7320870

35. Zhao Y Li A Jiang L Hybrid membrane-coated biomimetic nanoparticles (HM@BNPs): a multifunctional nanomaterial for biomedical applications Biomacromol 2021 22 8 3149 3167 10.1021/acs.biomac.1c00440 34225451 Zhao Y, Li A, Jiang L, et al. Hybrid membrane-coated biomimetic nanoparticles (HM@BNPs): a multifunctional nanomaterial for biomedical applications. Biomacromol. 2021;22(8):3149–67. 10.1021/acs.biomac.1c00440 34225451

36. Pitchaimani A Nguyen TDT Aryal S Natural killer cell membrane infused biomimetic liposomes for targeted tumor therapy Biomaterials 2018 160 124 137 10.1016/j.biomaterials.2018.01.018 29407341 Pitchaimani A, Nguyen TDT, Aryal S. Natural killer cell membrane infused biomimetic liposomes for targeted tumor therapy. Biomaterials. 2018;160:124–37. 29407341 10.1016/j.biomaterials.2018.01.018

37. Cheng S Xu C Jin Y Artificial mini dendritic cells boost T cell-based immunotherapy for ovarian cancer Adv Sci 2020 7 7 1903301 10.1002/advs.201903301 PMC7141030 32274314 Cheng S, Xu C, Jin Y, et al. Artificial mini dendritic cells boost T cell-based immunotherapy for ovarian cancer. Adv Sci. 2020;7(7):1903301. 10.1002/advs.201903301 PMC7141030 32274314

38. Mukker JK Singh RSP Pharmacokinetic modeling in nano-formulations: concept, implementation and challenges Curr Pharm Des 2018 24 43 5175 5180 10.2174/1381612825666190130141310 30706804 Mukker JK, Singh RSP. Pharmacokinetic modeling in nano-formulations: concept, implementation and challenges. Curr Pharm Des. 2018;24(43):5175–80. 30706804 10.2174/1381612825666190130141310

39. Chopra A. Cy5.5-Conjugated glycol chitosan-5β-cholanic acid nanoparticles. In Molecular Imaging and Contrast Agent Database (MICAD). Bethesda (MD): National Center for Biotechnology Information (US); 2004 22593949

40. Wang M Thanou M Targeting nanoparticles to cancer Pharmacol Res 2010 62 2 90 99 10.1016/j.phrs.2010.03.005 20380880 Wang M, Thanou M. Targeting nanoparticles to cancer. Pharmacol Res. 2010;62(2):90–9. 20380880 10.1016/j.phrs.2010.03.005

41. Belyaev IB Griaznova OY Yaremenko AV Beyond the EPR effect: Intravital microscopy analysis of nanoparticle drug delivery to tumors Adv Drug Deliv Rev 2025 219 115550 10.1016/j.addr.2025.115550 40021012 Belyaev IB, Griaznova OY, Yaremenko AV, et al. Beyond the EPR effect: Intravital microscopy analysis of nanoparticle drug delivery to tumors. Adv Drug Deliv Rev. 2025;219: 115550. 40021012 10.1016/j.addr.2025.115550

42. Wu X Hu JJ Yoon J Cell membrane as a promising therapeutic target: from materials design to biomedical applications Angew Chem Int Ed Engl 2024 63 18 e202400249 10.1002/anie.202400249 38372669 Wu X, Hu JJ, Yoon J. Cell membrane as a promising therapeutic target: from materials design to biomedical applications. Angew Chem Int Ed Engl. 2024;63(18): e202400249. 38372669 10.1002/anie.202400249

43. Zou D Wu Z Yi X Nanoparticle elasticity regulates the formation of cell membrane-coated nanoparticles and their nano-bio interactions Proc Natl Acad Sci USA 2023 120 1 e2214757120 10.1073/pnas.2214757120 36574680 PMC9910481 Zou D, Wu Z, Yi X, et al. Nanoparticle elasticity regulates the formation of cell membrane-coated nanoparticles and their nano-bio interactions. Proc Natl Acad Sci USA. 2023;120(1): e2214757120. 36574680 10.1073/pnas.2214757120 PMC9910481

44. Walkey CD Olsen JB Guo H Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake J Am Chem Soc 2012 134 4 2139 2147 10.1021/ja2084338 22191645 Walkey CD, Olsen JB, Guo H, et al. Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake. J Am Chem Soc. 2012;134(4):2139–47. 22191645 10.1021/ja2084338

45. Li Y Kröger M Liu WK Shape effect in cellular uptake of PEGylated nanoparticles: comparison between sphere, rod, cube and disk Nanoscale 2015 7 40 16631 16646 10.1039/C5NR02970H 26204104 Li Y, Kröger M, Liu WK. Shape effect in cellular uptake of PEGylated nanoparticles: comparison between sphere, rod, cube and disk. Nanoscale. 2015;7(40):16631–46. 26204104 10.1039/c5nr02970h

46. Parakhonskiy B Zyuzin MV Yashchenok A The influence of the size and aspect ratio of anisotropic, porous CaCO3 particles on their uptake by cells J Nanobiotechnol 2015 13 53 10.1186/s12951-015-0111-7 PMC4558630 26337452 Parakhonskiy B, Zyuzin MV, Yashchenok A, et al. The influence of the size and aspect ratio of anisotropic, porous CaCO3 particles on their uptake by cells. J Nanobiotechnol. 2015;13:53. 10.1186/s12951-015-0111-7 PMC4558630 26337452

47. Dong N Liu Z He H "Hook&Loop" multivalent interactions based on disk-shaped nanoparticles strengthen active targeting J Control Release 2023 354 279 293 10.1016/j.jconrel.2023.01.022 36641117 Dong N, Liu Z, He H, et al. “Hook&Loop” multivalent interactions based on disk-shaped nanoparticles strengthen active targeting. J Control Release. 2023;354:279–93. 36641117 10.1016/j.jconrel.2023.01.022

48. Nguyen LNM Lin ZP Sindhwani S The exit of nanoparticles from solid tumours Nat Mater 2023 22 10 1261 1272 10.1038/s41563-023-01630-0 37592029 Nguyen LNM, Lin ZP, Sindhwani S, et al. The exit of nanoparticles from solid tumours. Nat Mater. 2023;22(10):1261–72. 37592029 10.1038/s41563-023-01630-0

49. Liu J Zhou Y Lyu Q Targeted protein delivery based on stimuli-triggered nanomedicine Exploration 2024 4 3 20230025 10.1002/EXP.20230025 38939867 PMC11189579 Liu J, Zhou Y, Lyu Q, et al. Targeted protein delivery based on stimuli-triggered nanomedicine. Exploration. 2024;4(3):20230025. 38939867 10.1002/EXP.20230025 PMC11189579

50. Chen X Fan X Zhang Y Cooperative coordination-mediated multi-component self-assembly of "all-in-one" nanospike theranostic nano-platform for MRI-guided synergistic therapy against breast cancer Acta Pharm Sin B 2022 12 9 3710 3725 10.1016/j.apsb.2022.02.027 36176903 PMC9513557 Chen X, Fan X, Zhang Y, et al. Cooperative coordination-mediated multi-component self-assembly of “all-in-one” nanospike theranostic nano-platform for MRI-guided synergistic therapy against breast cancer. Acta Pharm Sin B. 2022;12(9):3710–25. 36176903 10.1016/j.apsb.2022.02.027 PMC9513557

51. Jeevanandam J Barhoum A Chan YS Review on nanoparticles and nanostructured materials: history, sources, toxicity and regulations Beilstein J Nanotechnol 2018 9 1050 1074 10.3762/bjnano.9.98 29719757 PMC5905289 Jeevanandam J, Barhoum A, Chan YS, et al. Review on nanoparticles and nanostructured materials: history, sources, toxicity and regulations. Beilstein J Nanotechnol. 2018;9:1050–74. 29719757 10.3762/bjnano.9.98 PMC5905289

52. Deng K, Luo Z, Tan L, et al. Self-assembly of anisotropic nanoparticles into functional superstructures. Chem Soc Rev. 2020. 10.1039/d0cs00541j 32692337

53. Li J Jia X Photo-controlled self-assembly of nanoparticles: a promising strategy for development of novel structures Nanomaterials 2023 13 18 10.3390/nano13182562 PMC10535597 37764591 Li J, Jia X. Photo-controlled self-assembly of nanoparticles: a promising strategy for development of novel structures. Nanomaterials. 2023;13:18. 10.3390/nano13182562 PMC10535597 37764591

54. Cheng S Grest GS Dispersing Nanoparticles in a Polymer Film via Solvent Evaporation ACS Macro Lett 2016 5 6 694 698 10.1021/acsmacrolett.6b00263 35614677 Cheng S, Grest GS. Dispersing Nanoparticles in a Polymer Film via Solvent Evaporation. ACS Macro Lett. 2016;5(6):694–8. 35614677 10.1021/acsmacrolett.6b00263

55. Iqbal M Zafar N Fessi H Double emulsion solvent evaporation techniques used for drug encapsulation Int J Pharm 2015 496 2 173 190 10.1016/j.ijpharm.2015.10.057 26522982 Iqbal M, Zafar N, Fessi H, et al. Double emulsion solvent evaporation techniques used for drug encapsulation. Int J Pharm. 2015;496(2):173–90. 26522982 10.1016/j.ijpharm.2015.10.057

56. Mosayebi J Kiyasatfar M Laurent S Synthesis, functionalization, and design of magnetic nanoparticles for theranostic applications Adv Healthc Mater 2017 6 23 1 10.1002/adhm.201700306 28990364 Mosayebi J, Kiyasatfar M, Laurent S. Synthesis, functionalization, and design of magnetic nanoparticles for theranostic applications. Adv Healthc Mater. 2017;6(23):1. 10.1002/adhm.201700306 28990364

57. Devalapally H Shenoy D Little S Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs: part 3. Therapeutic efficacy and safety studies in ovarian cancer xenograft model Cancer Chemother Pharmacol 2007 59 4 477 84 10.1007/s00280-006-0287-5 16862429 Devalapally H, Shenoy D, Little S, et al. Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs: part 3. Therapeutic efficacy and safety studies in ovarian cancer xenograft model. Cancer Chemother Pharmacol. 2007;59(4):477–84. 16862429 10.1007/s00280-006-0287-5

58. Bertrand N Wu J Xu X Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology Adv Drug Deliv Rev 2014 66 2 25 10.1016/j.addr.2013.11.009 24270007 PMC4219254 Bertrand N, Wu J, Xu X, et al. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv Drug Deliv Rev. 2014;66:2–25. 24270007 10.1016/j.addr.2013.11.009 PMC4219254

59. Maeda H Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity Adv Drug Deliv Rev 2015 91 3 6 10.1016/j.addr.2015.01.002 25579058 Maeda H. Toward a full understanding of the EPR effect in primary and metastatic tumors as well as issues related to its heterogeneity. Adv Drug Deliv Rev. 2015;91:3–6. 25579058 10.1016/j.addr.2015.01.002

60. Shi J Kantoff PW Wooster R Cancer nanomedicine: progress, challenges and opportunities Nat Rev Cancer 2017 17 1 20 37 10.1038/nrc.2016.108 27834398 PMC5575742 Shi J, Kantoff PW, Wooster R, et al. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer. 2017;17(1):20–37. 27834398 10.1038/nrc.2016.108 PMC5575742

61. Cornu R Béduneau A Martin H Influence of nanoparticles on liver tissue and hepatic functions: a review Toxicology 2020 430 152344 10.1016/j.tox.2019.152344 31843632 Cornu R, Béduneau A, Martin H. Influence of nanoparticles on liver tissue and hepatic functions: a review. Toxicology. 2020;430: 152344. 31843632 10.1016/j.tox.2019.152344

62. Önal Acet B Gül D Stauber RH A review for uncovering the "protein-nanoparticle alliance": implications of the protein corona for biomedical applications Nanomaterials 2024 14 10 10.3390/nano14100823 PMC11124003 38786780 Önal Acet B, Gül D, Stauber RH, et al. A review for uncovering the “protein-nanoparticle alliance”: implications of the protein corona for biomedical applications. Nanomaterials. 2024;14:10. 10.3390/nano14100823 PMC11124003 38786780

63. Chen F Wang G Griffin JI Complement proteins bind to nanoparticle protein corona and undergo dynamic exchange in vivo Nat Nanotechnol 2017 12 4 387 393 10.1038/nnano.2016.269 27992410 PMC5617637 Chen F, Wang G, Griffin JI, et al. Complement proteins bind to nanoparticle protein corona and undergo dynamic exchange in vivo. Nat Nanotechnol. 2017;12(4):387–93. 27992410 10.1038/nnano.2016.269 PMC5617637

64. Fröhlich E Cellular elimination of nanoparticles Environ Toxicol Pharmacol 2016 46 90 94 10.1016/j.etap.2016.07.003 27442891 Fröhlich E. Cellular elimination of nanoparticles. Environ Toxicol Pharmacol. 2016;46:90–4. 27442891 10.1016/j.etap.2016.07.003

65. Hoshyar N Gray S Han H The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction Nanomedicine 2016 11 6 673 692 10.2217/nnm.16.5 27003448 PMC5561790 Hoshyar N, Gray S, Han H, et al. The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction. Nanomedicine. 2016;11(6):673–92. 27003448 10.2217/nnm.16.5 PMC5561790

66. Poon W Zhang YN Ouyang B Elimination pathways of nanoparticles ACS Nano 2019 13 5 5785 5798 10.1021/acsnano.9b01383 30990673 Poon W, Zhang YN, Ouyang B, et al. Elimination pathways of nanoparticles. ACS Nano. 2019;13(5):5785–98. 30990673 10.1021/acsnano.9b01383

67. Zhang YN Poon W Tavares AJ Nanoparticle-liver interactions: cellular uptake and hepatobiliary elimination J Control Release 2016 240 332 348 10.1016/j.jconrel.2016.01.020 26774224 Zhang YN, Poon W, Tavares AJ, et al. Nanoparticle-liver interactions: cellular uptake and hepatobiliary elimination. J Control Release. 2016;240:332–48. 26774224 10.1016/j.jconrel.2016.01.020

68. Brand W Noorlander CW Giannakou C Nanomedicinal products: a survey on specific toxicity and side effects Int J Nanomedicine 2017 12 6107 6129 10.2147/IJN.S139687 28883724 PMC5574663 Brand W, Noorlander CW, Giannakou C, et al. Nanomedicinal products: a survey on specific toxicity and side effects. Int J Nanomedicine. 2017;12:6107–29. 28883724 10.2147/IJN.S139687 PMC5574663

69. Stone V Johnston H Schins RP Development of in vitro systems for nanotoxicology: methodological considerations Crit Rev Toxicol 2009 39 7 613 626 10.1080/10408440903120975 19650720 Stone V, Johnston H, Schins RP. Development of in vitro systems for nanotoxicology: methodological considerations. Crit Rev Toxicol. 2009;39(7):613–26. 19650720 10.1080/10408440903120975

70. Shiraishi K Yokoyama M Toxicity and immunogenicity concerns related to PEGylated-micelle carrier systems: a review Sci Technol Adv Mater 2019 20 1 324 336 10.1080/14686996.2019.1590126 31068982 PMC6493319 Shiraishi K, Yokoyama M. Toxicity and immunogenicity concerns related to PEGylated-micelle carrier systems: a review. Sci Technol Adv Mater. 2019;20(1):324–36. 31068982 10.1080/14686996.2019.1590126 PMC6493319

71. Chen J Mao L Jiang Y Revealing the In Situ behavior of aggregation-induced emission nanoparticles and their biometabolic effects via mass spectrometry imaging ACS Nano 2023 17 5 4463 4473 10.1021/acsnano.2c10058 36802559 Chen J, Mao L, Jiang Y, et al. Revealing the In Situ behavior of aggregation-induced emission nanoparticles and their biometabolic effects via mass spectrometry imaging. ACS Nano. 2023;17(5):4463–73. 36802559 10.1021/acsnano.2c10058

72. Portilho FL Helal-Neto E Cabezas SS Magnetic core mesoporous silica nanoparticles doped with dacarbazine and labelled with 99mTc for early and differential detection of metastatic melanoma by single photon emission computed tomography Artif Cells Nanomed Biotechnol 2018 46 sup1 1080 1087 10.1080/21691401.2018.1443941 29482360 Portilho FL, Helal-Neto E, Cabezas SS, et al. Magnetic core mesoporous silica nanoparticles doped with dacarbazine and labelled with 99mTc for early and differential detection of metastatic melanoma by single photon emission computed tomography. Artif Cells Nanomed Biotechnol. 2018;46(sup1):1080–7. 29482360 10.1080/21691401.2018.1443941

73. Li P Wang D Hu J The role of imaging in targeted delivery of nanomedicine for cancer therapy Adv Drug Deliv Rev 2022 189 114447 10.1016/j.addr.2022.114447 35863515 Li P, Wang D, Hu J, et al. The role of imaging in targeted delivery of nanomedicine for cancer therapy. Adv Drug Deliv Rev. 2022;189: 114447. 35863515 10.1016/j.addr.2022.114447

74. Wang D Pan Y Chen W Nanodrugs targeting key factors of ferroptosis regulation for enhanced treatment of osteoarthritis Adv Sci 2025 12 11 e2412817 10.1002/advs.202412817 PMC11923906 39840543 Wang D, Pan Y, Chen W, et al. Nanodrugs targeting key factors of ferroptosis regulation for enhanced treatment of osteoarthritis. Adv Sci. 2025;12(11): e2412817. 10.1002/advs.202412817 PMC11923906 39840543

75. The L GLOBOCAN 2018: counting the toll of cancer Lancet 2018 392 10152 985 10.1016/S0140-6736(18)32252-9 30264708 The L. GLOBOCAN 2018: counting the toll of cancer. Lancet. 2018;392(10152):985. 30264708 10.1016/S0140-6736(18)32252-9

76. Gotwals P Cameron S Cipolletta D Prospects for combining targeted and conventional cancer therapy with immunotherapy Nat Rev Cancer 2017 17 5 286 301 10.1038/nrc.2017.17 28338065 Gotwals P, Cameron S, Cipolletta D, et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy. Nat Rev Cancer. 2017;17(5):286–301. 28338065 10.1038/nrc.2017.17

77. Romanini A Tanganelli L Carnino F First-line chemotherapy with epidoxorubicin, paclitaxel, and carboplatin for the treatment of advanced epithelial ovarian cancer patients Gynecol Oncol 2003 89 3 354 359 10.1016/S0090-8258(03)00128-8 12798695 Romanini A, Tanganelli L, Carnino F, et al. First-line chemotherapy with epidoxorubicin, paclitaxel, and carboplatin for the treatment of advanced epithelial ovarian cancer patients. Gynecol Oncol. 2003;89(3):354–9. 12798695 10.1016/s0090-8258(03)00128-8

78. Wu Q Yang Z Nie Y Multi-drug resistance in cancer chemotherapeutics: mechanisms and lab approaches Cancer Lett 2014 347 2 159 166 10.1016/j.canlet.2014.03.013 24657660 Wu Q, Yang Z, Nie Y, et al. Multi-drug resistance in cancer chemotherapeutics: mechanisms and lab approaches. Cancer Lett. 2014;347(2):159–66. 24657660 10.1016/j.canlet.2014.03.013

79. Brannon-Peppas L Blanchette JO Nanoparticle and targeted systems for cancer therapy Adv Drug Deliv Rev 2004 56 11 1649 1659 10.1016/j.addr.2004.02.014 15350294 Brannon-Peppas L, Blanchette JO. Nanoparticle and targeted systems for cancer therapy. Adv Drug Deliv Rev. 2004;56(11):1649–59. 15350294 10.1016/j.addr.2004.02.014

80. Janjic A Cayoren M Akduman I SAFE: a novel microwave imaging system design for breast cancer screening and early detection-clinical evaluation Diagnostics 2021 11 3 10.3390/diagnostics11030533 PMC8002280 33809770 Janjic A, Cayoren M, Akduman I, et al. SAFE: a novel microwave imaging system design for breast cancer screening and early detection-clinical evaluation. Diagnostics. 2021;11:3. 10.3390/diagnostics11030533 PMC8002280 33809770

81. Kuai R Li D Chen YE High-density lipoproteins: nature's multifunctional nanoparticles ACS Nano 2016 10 3 3015 3041 10.1021/acsnano.5b07522 26889958 PMC4918468 Kuai R, Li D, Chen YE, et al. High-density lipoproteins: nature’s multifunctional nanoparticles. ACS Nano. 2016;10(3):3015–41. 26889958 10.1021/acsnano.5b07522 PMC4918468

82. Wang X, Lin L, Liu R, et al. Anisotropy in shape and ligand‐conjugation of hybrid nanoparticulates manipulates the mode of bio–nano interaction and its outcome. 2017;27(31) : 1700406.

83. Zheng G Chen J Li H Rerouting lipoprotein nanoparticles to selected alternate receptors for the targeted delivery of cancer diagnostic and therapeutic agents Proc Natl Acad Sci USA 2005 102 49 17757 17762 10.1073/pnas.0508677102 16306263 PMC1308912 Zheng G, Chen J, Li H, et al. Rerouting lipoprotein nanoparticles to selected alternate receptors for the targeted delivery of cancer diagnostic and therapeutic agents. Proc Natl Acad Sci USA. 2005;102(49):17757–62. 16306263 10.1073/pnas.0508677102 PMC1308912

84. Bariwal J Ma H Altenberg GA Nanodiscs: a versatile nanocarrier platform for cancer diagnosis and treatment Chem Soc Rev 2022 51 5 1702 1728 10.1039/D1CS01074C 35156110 Bariwal J, Ma H, Altenberg GA, et al. Nanodiscs: a versatile nanocarrier platform for cancer diagnosis and treatment. Chem Soc Rev. 2022;51(5):1702–28. 35156110 10.1039/d1cs01074c

85. Feng H Wang M Wu C High scavenger receptor class B type I expression is related to tumor aggressiveness and poor prognosis in lung adenocarcinoma: a STROBE compliant article Medicine 2018 97 13 e0203 10.1097/MD.0000000000010203 29595658 PMC5895397 Feng H, Wang M, Wu C, et al. High scavenger receptor class B type I expression is related to tumor aggressiveness and poor prognosis in lung adenocarcinoma: a STROBE compliant article. Medicine. 2018;97(13): e0203. 29595658 10.1097/MD.0000000000010203 PMC5895397

86. Tang J Kuai R Yuan W Effect of size and pegylation of liposomes and peptide-based synthetic lipoproteins on tumor targeting Nanomedicine 2017 13 6 1869 1878 10.1016/j.nano.2017.04.009 28434931 PMC5554706 Tang J, Kuai R, Yuan W, et al. Effect of size and pegylation of liposomes and peptide-based synthetic lipoproteins on tumor targeting. Nanomedicine. 2017;13(6):1869–78. 28434931 10.1016/j.nano.2017.04.009 PMC5554706

87. Chen W Jarzyna PA van Tilborg GA RGD peptide functionalized and reconstituted high-density lipoprotein nanoparticles as a versatile and multimodal tumor targeting molecular imaging probe Faseb J 2010 24 6 1689 1699 10.1096/fj.09-139865 20075195 PMC2874482 Chen W, Jarzyna PA, van Tilborg GA, et al. RGD peptide functionalized and reconstituted high-density lipoprotein nanoparticles as a versatile and multimodal tumor targeting molecular imaging probe. Faseb J. 2010;24(6):1689–99. 20075195 10.1096/fj.09-139865 PMC2874482

88. Li W Yu H Ding D Cold atmospheric plasma and iron oxide-based magnetic nanoparticles for synergetic lung cancer therapy Free Radical Biol Med 2019 130 71 81 10.1016/j.freeradbiomed.2018.10.429 30342190 Li W, Yu H, Ding D, et al. Cold atmospheric plasma and iron oxide-based magnetic nanoparticles for synergetic lung cancer therapy. Free Radical Biol Med. 2019;130:71–81. 30342190 10.1016/j.freeradbiomed.2018.10.429

89. Gao P Mei C He L Designing multifunctional cancer-targeted nanosystem for magnetic resonance molecular imaging-guided theranostics of lung cancer Drug Deliv 2018 25 1 1811 1825 10.1080/10717544.2018.1494224 30465437 PMC6263109 Gao P, Mei C, He L, et al. Designing multifunctional cancer-targeted nanosystem for magnetic resonance molecular imaging-guided theranostics of lung cancer. Drug Deliv. 2018;25(1):1811–25. 30465437 10.1080/10717544.2018.1494224 PMC6263109

90. Tiwari N Gheldof A Tatari M EMT as the ultimate survival mechanism of cancer cells Semin Cancer Biol 2012 22 3 194 207 10.1016/j.semcancer.2012.02.013 22406545 Tiwari N, Gheldof A, Tatari M, et al. EMT as the ultimate survival mechanism of cancer cells. Semin Cancer Biol. 2012;22(3):194–207. 22406545 10.1016/j.semcancer.2012.02.013

91. Dongre A Weinberg RA New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer Nat Rev Mol Cell Biol 2019 20 2 69 84 10.1038/s41580-018-0080-4 30459476 Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2019;20(2):69–84. 30459476 10.1038/s41580-018-0080-4

92. Diepenbruck M Christofori G Epithelial-mesenchymal transition (EMT) and metastasis: yes, no, maybe? Curr Opin Cell Biol 2016 43 7 13 10.1016/j.ceb.2016.06.002 27371787 Diepenbruck M, Christofori G. Epithelial-mesenchymal transition (EMT) and metastasis: yes, no, maybe? Curr Opin Cell Biol. 2016;43:7–13. 27371787 10.1016/j.ceb.2016.06.002

93. Ang HL Mohan CD Shanmugam MK Mechanism of epithelial-mesenchymal transition in cancer and its regulation by natural compounds Med Res Rev 2023 43 4 1141 1200 10.1002/med.21948 36929669 Ang HL, Mohan CD, Shanmugam MK, et al. Mechanism of epithelial-mesenchymal transition in cancer and its regulation by natural compounds. Med Res Rev. 2023;43(4):1141–200. 36929669 10.1002/med.21948

94. Balakrishnan S Bhat FA Raja Singh P Gold nanoparticle-conjugated quercetin inhibits epithelial-mesenchymal transition, angiogenesis and invasiveness via EGFR/VEGFR-2-mediated pathway in breast cancer Cell Prolif 2016 49 6 678 697 10.1111/cpr.12296 27641938 PMC6496551 Balakrishnan S, Bhat FA, Raja Singh P, et al. Gold nanoparticle-conjugated quercetin inhibits epithelial-mesenchymal transition, angiogenesis and invasiveness via EGFR/VEGFR-2-mediated pathway in breast cancer. Cell Prolif. 2016;49(6):678–97. 27641938 10.1111/cpr.12296 PMC6496551

95. Agarwalla P Mukherjee S Sreedhar B Glucocorticoid receptor-mediated delivery of nano gold-withaferin conjugates for reversal of epithelial-to-mesenchymal transition and tumor regression Nanomedicine 2016 11 19 2529 2546 10.2217/nnm-2016-0224 27622735 Agarwalla P, Mukherjee S, Sreedhar B, et al. Glucocorticoid receptor-mediated delivery of nano gold-withaferin conjugates for reversal of epithelial-to-mesenchymal transition and tumor regression. Nanomedicine. 2016;11(19):2529–46. 27622735 10.2217/nnm-2016-0224

96. Baghi N Bakhshinejad B Keshavarz R Dendrosomal nanocurcumin and exogenous p53 can act synergistically to elicit anticancer effects on breast cancer cells Gene 2018 670 55 62 10.1016/j.gene.2018.05.025 29753810 Baghi N, Bakhshinejad B, Keshavarz R, et al. Dendrosomal nanocurcumin and exogenous p53 can act synergistically to elicit anticancer effects on breast cancer cells. Gene. 2018;670:55–62. 29753810 10.1016/j.gene.2018.05.025

97. Kumari M Ray L Purohit MP Curcumin loading potentiates the chemotherapeutic efficacy of selenium nanoparticles in HCT116 cells and Ehrlich's ascites carcinoma bearing mice Eur J Pharm Biopharm 2017 117 346 362 10.1016/j.ejpb.2017.05.003 28499854 Kumari M, Ray L, Purohit MP, et al. Curcumin loading potentiates the chemotherapeutic efficacy of selenium nanoparticles in HCT116 cells and Ehrlich’s ascites carcinoma bearing mice. Eur J Pharm Biopharm. 2017;117:346–62. 28499854 10.1016/j.ejpb.2017.05.003

98. Kumari M Purohit MP Patnaik S Curcumin loaded selenium nanoparticles synergize the anticancer potential of doxorubicin contained in self-assembled, cell receptor targeted nanoparticles Eur J Pharm Biopharm 2018 130 185 199 10.1016/j.ejpb.2018.06.030 29969665 Kumari M, Purohit MP, Patnaik S, et al. Curcumin loaded selenium nanoparticles synergize the anticancer potential of doxorubicin contained in self-assembled, cell receptor targeted nanoparticles. Eur J Pharm Biopharm. 2018;130:185–99. 29969665 10.1016/j.ejpb.2018.06.030

99. Zhang S Ji X Liu Z Bimetallic nanoplatforms for prostate cancer treatment by interfering cellular communication J Am Chem Soc 2024 146 32 22530 22540 10.1021/jacs.4c06267 39082227 Zhang S, Ji X, Liu Z, et al. Bimetallic nanoplatforms for prostate cancer treatment by interfering cellular communication. J Am Chem Soc. 2024;146(32):22530–40. 39082227 10.1021/jacs.4c06267

100. Wu J The enhanced permeability and retention (EPR) effect: the significance of the concept and methods to enhance its application J Pers Med 2021 11 8 771 10.3390/jpm11080771 34442415 PMC8402171 Wu J. The enhanced permeability and retention (EPR) effect: the significance of the concept and methods to enhance its application. J Pers Med. 2021;11(8):771. 34442415 10.3390/jpm11080771 PMC8402171

101. Danhier F Feron O Préat V To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery J Control Release 2010 148 2 135 146 10.1016/j.jconrel.2010.08.027 20797419 Danhier F, Feron O, Préat V. To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J Control Release. 2010;148(2):135–46. 20797419 10.1016/j.jconrel.2010.08.027

102. Muggia F Kudlowitz D Novel taxanes Anticancer Drugs 2014 25 5 593 598 10.1097/CAD.0000000000000053 24374330 Muggia F, Kudlowitz D. Novel taxanes. Anticancer Drugs. 2014;25(5):593–8. 24374330 10.1097/CAD.0000000000000053

103. Tan L Peng J Zhao Q A novel MPEG-PDLLA-PLL copolymer for docetaxel delivery in breast cancer therapy Theranostics 2017 7 10 2652 2672 10.7150/thno.19680 28819454 PMC5558560 Tan L, Peng J, Zhao Q, et al. A novel MPEG-PDLLA-PLL copolymer for docetaxel delivery in breast cancer therapy. Theranostics. 2017;7(10):2652–72. 28819454 10.7150/thno.19680 PMC5558560

104. Xiao W Suby N Xiao K Extremely long tumor retention, multi-responsive boronate crosslinked micelles with superior therapeutic efficacy for ovarian cancer J Control Release 2017 264 169 179 10.1016/j.jconrel.2017.08.028 28847739 PMC5632596 Xiao W, Suby N, Xiao K, et al. Extremely long tumor retention, multi-responsive boronate crosslinked micelles with superior therapeutic efficacy for ovarian cancer. J Control Release. 2017;264:169–79. 28847739 10.1016/j.jconrel.2017.08.028 PMC5632596

105. He H Liu L Morin EE Survey of clinical translation of cancer nanomedicines—lessons learned from successes and failures Acc Chem Res 2019 52 9 2445 2461 10.1021/acs.accounts.9b00228 31424909 He H, Liu L, Morin EE, et al. Survey of clinical translation of cancer nanomedicines—lessons learned from successes and failures. Acc Chem Res. 2019;52(9):2445–61. 31424909 10.1021/acs.accounts.9b00228

106. Youn YS Bae YH Perspectives on the past, present, and future of cancer nanomedicine Adv Drug Deliv Rev 2018 130 3 11 10.1016/j.addr.2018.05.008 29778902 Youn YS, Bae YH. Perspectives on the past, present, and future of cancer nanomedicine. Adv Drug Deliv Rev. 2018;130:3–11. 29778902 10.1016/j.addr.2018.05.008

107. Wang Y van Steenbergen MJ Beztsinna N Biotin-decorated all-HPMA polymeric micelles for paclitaxel delivery J Control Release 2020 328 970 984 10.1016/j.jconrel.2020.09.013 32926885 Wang Y, van Steenbergen MJ, Beztsinna N, et al. Biotin-decorated all-HPMA polymeric micelles for paclitaxel delivery. J Control Release. 2020;328:970–84. 32926885 10.1016/j.jconrel.2020.09.013

108. Liu L Deng Y Zheng Z Hsp90 inhibitor STA9090 sensitizes hepatocellular carcinoma to hyperthermia-induced DNA damage by suppressing DNA-PKcs protein stability and mRNA transcription Mol Cancer Ther 2021 20 10 1880 1892 10.1158/1535-7163.MCT-21-0215 34376581 PMC8513797 Liu L, Deng Y, Zheng Z, et al. Hsp90 inhibitor STA9090 sensitizes hepatocellular carcinoma to hyperthermia-induced DNA damage by suppressing DNA-PKcs protein stability and mRNA transcription. Mol Cancer Ther. 2021;20(10):1880–92. 34376581 10.1158/1535-7163.MCT-21-0215 PMC8513797

109. Jia L Yang H Liu Y Targeted delivery of HSP90 inhibitors for efficient therapy of CD44-positive acute myeloid leukemia and solid tumor-colon cancer J Nanobiotechnol 2024 22 1 198 10.1186/s12951-024-02460-1 PMC11036589 38649957 Jia L, Yang H, Liu Y, et al. Targeted delivery of HSP90 inhibitors for efficient therapy of CD44-positive acute myeloid leukemia and solid tumor-colon cancer. J Nanobiotechnol. 2024;22(1):198. 10.1186/s12951-024-02460-1 PMC11036589 38649957

110. Dash P Piras AM Dash M Cell membrane coated nanocarriers - an efficient biomimetic platform for targeted therapy J Control Release 2020 327 546 570 10.1016/j.jconrel.2020.09.012 32911013 Dash P, Piras AM, Dash M. Cell membrane coated nanocarriers - an efficient biomimetic platform for targeted therapy. J Control Release. 2020;327:546–70. 32911013 10.1016/j.jconrel.2020.09.012

111. Li H, Lu J, Yan C, et al. Tumor cell membrane-coated biomimetic nanoplatform for homologous targeted therapy of colorectal carcinoma. Int J Polym Mater. 2019 : 1–10.

112. Baxevanis CN Perez SA Papamichail M Cancer immunotherapy Crit Rev Clin Lab Sci 2009 46 4 167 189 10.1080/10408360902937809 19650714 Baxevanis CN, Perez SA, Papamichail M. Cancer immunotherapy. Crit Rev Clin Lab Sci. 2009;46(4):167–89. 19650714 10.1080/10408360902937809

113. Yan S Luo Z Li Z Improving cancer immunotherapy outcomes using biomaterials Angew Chem Int Ed Engl 2020 59 40 17332 17343 10.1002/anie.202002780 32297434 Yan S, Luo Z, Li Z, et al. Improving cancer immunotherapy outcomes using biomaterials. Angew Chem Int Ed Engl. 2020;59(40):17332–43. 32297434 10.1002/anie.202002780

114. Sterner RC Sterner RM CAR-T cell therapy: current limitations and potential strategies Blood Cancer J 2021 11 4 69 10.1038/s41408-021-00459-7 33824268 PMC8024391 Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11(4):69. 33824268 10.1038/s41408-021-00459-7 PMC8024391

115. Singh AK McGuirk JP CAR T cells: continuation in a revolution of immunotherapy Lancet Oncol 2020 21 3 e168 e178 10.1016/S1470-2045(19)30823-X 32135120 Singh AK, McGuirk JP. CAR T cells: continuation in a revolution of immunotherapy. Lancet Oncol. 2020;21(3):e168–78. 32135120 10.1016/S1470-2045(19)30823-X

116. Martin JD Cabral H Stylianopoulos T Improving cancer immunotherapy using nanomedicines: progress, opportunities and challenges Nat Rev Clin Oncol 2020 17 4 251 266 10.1038/s41571-019-0308-z 32034288 PMC8272676 Martin JD, Cabral H, Stylianopoulos T, et al. Improving cancer immunotherapy using nanomedicines: progress, opportunities and challenges. Nat Rev Clin Oncol. 2020;17(4):251–66. 32034288 10.1038/s41571-019-0308-z PMC8272676

117. Wang L Xu H Weng L Activation of cancer immunotherapy by nanomedicine Front Pharmacol 2022 13 1041073 10.3389/fphar.2022.1041073 36618938 PMC9814015 Wang L, Xu H, Weng L, et al. Activation of cancer immunotherapy by nanomedicine. Front Pharmacol. 2022;13:1041073. 36618938 10.3389/fphar.2022.1041073 PMC9814015

118. Kennedy LB Salama AKS A review of cancer immunotherapy toxicity CA Cancer J Clin 2020 70 2 86 104 10.3322/caac.21596 31944278 Kennedy LB, Salama AKS. A review of cancer immunotherapy toxicity. CA Cancer J Clin. 2020;70(2):86–104. 31944278 10.3322/caac.21596

119. Liu YT Sun ZJ Turning cold tumors into hot tumors by improving T-cell infiltration Theranostics 2021 11 11 5365 5386 10.7150/thno.58390 33859752 PMC8039952 Liu YT, Sun ZJ. Turning cold tumors into hot tumors by improving T-cell infiltration. Theranostics. 2021;11(11):5365–86. 33859752 10.7150/thno.58390 PMC8039952

120. Zhang Y Zheng J Functions of immune checkpoint molecules beyond immune evasion Adv Exp Med Biol 2020 1248 201 226 10.1007/978-981-15-3266-5_9 32185712 Zhang Y, Zheng J. Functions of immune checkpoint molecules beyond immune evasion. Adv Exp Med Biol. 2020;1248:201–26. 32185712 10.1007/978-981-15-3266-5_9

121. Sanaei MJ Pourbagheri-Sigaroodi A Kaveh V The application of nano-medicine to overcome the challenges related to immune checkpoint blockades in cancer immunotherapy: recent advances and opportunities Crit Rev Oncol Hematol 2021 157 103160 10.1016/j.critrevonc.2020.103160 33220601 Sanaei MJ, Pourbagheri-Sigaroodi A, Kaveh V, et al. The application of nano-medicine to overcome the challenges related to immune checkpoint blockades in cancer immunotherapy: recent advances and opportunities. Crit Rev Oncol Hematol. 2021;157: 103160. 33220601 10.1016/j.critrevonc.2020.103160

122. Kapadia CH Perry JL Tian S Nanoparticulate immunotherapy for cancer J Control Release 2015 219 167 180 10.1016/j.jconrel.2015.09.062 26432555 Kapadia CH, Perry JL, Tian S, et al. Nanoparticulate immunotherapy for cancer. J Control Release. 2015;219:167–80. 26432555 10.1016/j.jconrel.2015.09.062

123. Larkin J Chiarion-Sileni V Gonzalez R Five-year survival with combined nivolumab and ipilimumab in advanced melanoma N Engl J Med 2019 381 16 1535 1546 10.1056/NEJMoa1910836 31562797 Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535–46. 31562797 10.1056/NEJMoa1910836

124. André T Lonardi S Wong KYM Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142 Ann Oncol 2022 33 10 1052 1060 10.1016/j.annonc.2022.06.008 35764271 André T, Lonardi S, Wong KYM, et al. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142. Ann Oncol. 2022;33(10):1052–60. 35764271 10.1016/j.annonc.2022.06.008

125. Hellmann MD Paz-Ares L Bernabe Caro R Nivolumab plus ipilimumab in advanced non-small-cell lung cancer N Engl J Med 2019 381 21 2020 2031 10.1056/NEJMoa1910231 31562796 Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381(21):2020–31. 31562796 10.1056/NEJMoa1910231

126. Chirnomas D Hornberger KR Crews CM Protein degraders enter the clinic - a new approach to cancer therapy Nat Rev Clin Oncol 2023 20 4 265 278 10.1038/s41571-023-00736-3 36781982 PMC11698446 Chirnomas D, Hornberger KR, Crews CM. Protein degraders enter the clinic - a new approach to cancer therapy. Nat Rev Clin Oncol. 2023;20(4):265–78. 36781982 10.1038/s41571-023-00736-3 PMC11698446

127. Bondeson DP Mares A Smith IE Catalytic in vivo protein knockdown by small-molecule PROTACs Nat Chem Biol 2015 11 8 611 617 10.1038/nchembio.1858 26075522 PMC4629852 Bondeson DP, Mares A, Smith IE, et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat Chem Biol. 2015;11(8):611–7. 26075522 10.1038/nchembio.1858 PMC4629852

128. Chen Y Tandon I Heelan W Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation Chem Soc Rev 2022 51 13 5330 5350 10.1039/D1CS00762A 35713468 PMC9382890 Chen Y, Tandon I, Heelan W, et al. Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation. Chem Soc Rev. 2022;51(13):5330–50. 35713468 10.1039/d1cs00762a PMC9382890

129. Yang L Yang Y Zhang J Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy Signal Transduct Target Ther 2024 9 1 275 10.1038/s41392-024-01983-1 39419977 PMC11486899 Yang L, Yang Y, Zhang J, et al. Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy. Signal Transduct Target Ther. 2024;9(1):275. 39419977 10.1038/s41392-024-01983-1 PMC11486899

130. Gauthier J Yakoub-Agha I Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: clinical data to date, current limitations and perspectives Curr Res Transl Med 2017 65 3 93 102 28988742 10.1016/j.retram.2017.08.003 Gauthier J, Yakoub-Agha I. Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: clinical data to date, current limitations and perspectives. Curr Res Transl Med. 2017;65(3):93–102. 28988742 10.1016/j.retram.2017.08.003

131. Kosti P Maher J Arnold JN Perspectives on chimeric antigen receptor T-cell immunotherapy for solid tumors Front Immunol 2018 9 1104 10.3389/fimmu.2018.01104 29872437 PMC5972325 Kosti P, Maher J, Arnold JN. Perspectives on chimeric antigen receptor T-cell immunotherapy for solid tumors. Front Immunol. 2018;9:1104. 29872437 10.3389/fimmu.2018.01104 PMC5972325

132. Tang L Zheng Y Melo MB Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery Nat Biotechnol 2018 36 8 707 716 10.1038/nbt.4181 29985479 PMC6078803 Tang L, Zheng Y, Melo MB, et al. Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. Nat Biotechnol. 2018;36(8):707–16. 29985479 10.1038/nbt.4181 PMC6078803

133. Luo Y Chen Z Sun M IL-12 nanochaperone-engineered CAR T cell for robust tumor-immunotherapy Biomaterials 2022 281 121341 10.1016/j.biomaterials.2021.121341 34995901 Luo Y, Chen Z, Sun M, et al. IL-12 nanochaperone-engineered CAR T cell for robust tumor-immunotherapy. Biomaterials. 2022;281: 121341. 34995901 10.1016/j.biomaterials.2021.121341

134. Sivaram AJ Wardiana A Howard CB Recent advances in the generation of antibody-nanomaterial conjugates Adv Healthc Mater 2018 7 1 1 10.1002/adhm.201700607 28961378 Sivaram AJ, Wardiana A, Howard CB, et al. Recent advances in the generation of antibody-nanomaterial conjugates. Adv Healthc Mater. 2018;7(1):1. 10.1002/adhm.201700607 28961378

135. Richards DA Maruani A Chudasama V Antibody fragments as nanoparticle targeting ligands: a step in the right direction Chem Sci 2017 8 1 63 77 10.1039/C6SC02403C 28451149 PMC5304706 Richards DA, Maruani A, Chudasama V. Antibody fragments as nanoparticle targeting ligands: a step in the right direction. Chem Sci. 2017;8(1):63–77. 28451149 10.1039/c6sc02403c PMC5304706

136. Cheng Z Al Zaki A Hui JZ Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities Science 2012 338 6109 903 910 10.1126/science.1226338 23161990 PMC3660151 Cheng Z, Al Zaki A, Hui JZ, et al. Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities. Science. 2012;338(6109):903–10. 23161990 10.1126/science.1226338 PMC3660151

137. Acharya S Dilnawaz F Sahoo SK Targeted epidermal growth factor receptor nanoparticle bioconjugates for breast cancer therapy Biomaterials 2009 30 29 5737 5750 10.1016/j.biomaterials.2009.07.008 19631377 Acharya S, Dilnawaz F, Sahoo SK. Targeted epidermal growth factor receptor nanoparticle bioconjugates for breast cancer therapy. Biomaterials. 2009;30(29):5737–50. 19631377 10.1016/j.biomaterials.2009.07.008

138. Saniee F Shabani Ravari N Goodarzi N Glutamate-urea-based PSMA-targeted PLGA nanoparticles for prostate cancer delivery of docetaxel Pharm Dev Technol 2021 26 4 381 389 10.1080/10837450.2021.1875238 33538232 Saniee F, Shabani Ravari N, Goodarzi N, et al. Glutamate-urea-based PSMA-targeted PLGA nanoparticles for prostate cancer delivery of docetaxel. Pharm Dev Technol. 2021;26(4):381–9. 33538232 10.1080/10837450.2021.1875238

139. Dhritlahre RK Saneja A Recent advances in HER2-targeted delivery for cancer therapy Drug Discov Today 2021 26 5 1319 1329 10.1016/j.drudis.2020.12.014 33359114 Dhritlahre RK, Saneja A. Recent advances in HER2-targeted delivery for cancer therapy. Drug Discov Today. 2021;26(5):1319–29. 33359114 10.1016/j.drudis.2020.12.014

140. Nieto C Vega MA Martín Del Valle EM Trastuzumab: more than a guide in HER2-positive cancer nanomedicine Nanomaterials 2020 10 9 1 10.3390/nano10091674 PMC7557948 32859026 Nieto C, Vega MA, Martín Del Valle EM. Trastuzumab: more than a guide in HER2-positive cancer nanomedicine. Nanomaterials. 2020;10(9):1. 10.3390/nano10091674 PMC7557948 32859026

141. Liu Y Li K Liu B A strategy for precision engineering of nanoparticles of biodegradable copolymers for quantitative control of targeted drug delivery Biomaterials 2010 31 35 9145 9155 10.1016/j.biomaterials.2010.08.053 20864169 Liu Y, Li K, Liu B, et al. A strategy for precision engineering of nanoparticles of biodegradable copolymers for quantitative control of targeted drug delivery. Biomaterials. 2010;31(35):9145–55. 20864169 10.1016/j.biomaterials.2010.08.053

142. Abedin MR Powers K Aiardo R Antibody-drug nanoparticle induces synergistic treatment efficacies in HER2 positive breast cancer cells Sci Rep 2021 11 1 7347 10.1038/s41598-021-86762-6 33795712 PMC8016985 Abedin MR, Powers K, Aiardo R, et al. Antibody-drug nanoparticle induces synergistic treatment efficacies in HER2 positive breast cancer cells. Sci Rep. 2021;11(1):7347. 33795712 10.1038/s41598-021-86762-6 PMC8016985

143. Gan J Lei J Li Y Manganese oxide-incorporated hybrid lipid nanoparticles amplify the potency of mrna vaccine via oxygen generation and STING activation J Am Chem Soc 2024 146 47 32689 32700 10.1021/jacs.4c12166 39552027 Gan J, Lei J, Li Y, et al. Manganese oxide-incorporated hybrid lipid nanoparticles amplify the potency of mrna vaccine via oxygen generation and STING activation. J Am Chem Soc. 2024;146(47):32689–700. 39552027 10.1021/jacs.4c12166

144. Rana PS Ignatz-Hoover JJ Guo C Immunoproteasome activation expands the MHC class I immunopeptidome, unmasks neoantigens, and enhances T-cell anti-myeloma activity Mol Cancer Ther 2024 23 12 1743 1760 10.1158/1535-7163.MCT-23-0931 39210605 PMC11612626 Rana PS, Ignatz-Hoover JJ, Guo C, et al. Immunoproteasome activation expands the MHC class I immunopeptidome, unmasks neoantigens, and enhances T-cell anti-myeloma activity. Mol Cancer Ther. 2024;23(12):1743–60. 39210605 10.1158/1535-7163.MCT-23-0931 PMC11612626

145. Haist M Mailänder V Bros M Nanodrugs targeting T cells in tumor therapy Front Immunol 2022 13 912594 10.3389/fimmu.2022.912594 35693776 PMC9174908 Haist M, Mailänder V, Bros M. Nanodrugs targeting T cells in tumor therapy. Front Immunol. 2022;13: 912594. 35693776 10.3389/fimmu.2022.912594 PMC9174908

146. Vinay DS Ryan EP Pawelec G Immune evasion in cancer: mechanistic basis and therapeutic strategies Semin Cancer Biol 2015 35 Suppl S185 S198 10.1016/j.semcancer.2015.03.004 25818339 Vinay DS, Ryan EP, Pawelec G, et al. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol. 2015;35(Suppl):S185–98. 25818339 10.1016/j.semcancer.2015.03.004

147. Tan Y Chen H Gou X Tumor vaccines: toward multidimensional anti-tumor therapies Hum Vaccin Immunother 2023 19 3 2271334 10.1080/21645515.2023.2271334 37905395 PMC10760370 Tan Y, Chen H, Gou X, et al. Tumor vaccines: toward multidimensional anti-tumor therapies. Hum Vaccin Immunother. 2023;19(3):2271334. 37905395 10.1080/21645515.2023.2271334 PMC10760370

148. Liu T Yao W Sun W Components, formulations, deliveries, and combinations of tumor vaccines ACS Nano 2024 18 29 18801 18833 10.1021/acsnano.4c05065 38979917 Liu T, Yao W, Sun W, et al. Components, formulations, deliveries, and combinations of tumor vaccines. ACS Nano. 2024;18(29):18801–33. 38979917 10.1021/acsnano.4c05065

149. Zhao Y Song D Wang Z Antitumour vaccination via the targeted proteolysis of antigens isolated from tumour lysates Nat Biomed Eng 2024 9 2 234 248 10.1038/s41551-024-01285-5 39609559 Zhao Y, Song D, Wang Z, et al. Antitumour vaccination via the targeted proteolysis of antigens isolated from tumour lysates. Nat Biomed Eng. 2024;9(2):234–48. 39609559 10.1038/s41551-024-01285-5

150. Hui L Chen Y Tumor microenvironment: sanctuary of the devil Cancer Lett 2015 368 1 7 13 10.1016/j.canlet.2015.07.039 26276713 Hui L, Chen Y. Tumor microenvironment: sanctuary of the devil. Cancer Lett. 2015;368(1):7–13. 26276713 10.1016/j.canlet.2015.07.039

151. Sun Y Translational horizons in the tumor microenvironment: harnessing breakthroughs and targeting cures Med Res Rev 2015 35 2 408 436 10.1002/med.21338 25588753 PMC4374701 Sun Y. Translational horizons in the tumor microenvironment: harnessing breakthroughs and targeting cures. Med Res Rev. 2015;35(2):408–36. 25588753 10.1002/med.21338 PMC4374701

152. Magnon C Hall SJ Lin J Autonomic nerve development contributes to prostate cancer progression Science 2013 341 6142 1236361 10.1126/science.1236361 23846904 Magnon C, Hall SJ, Lin J, et al. Autonomic nerve development contributes to prostate cancer progression. Science. 2013;341(6142):1236361. 23846904 10.1126/science.1236361

153. Hanahan D Monje M Cancer hallmarks intersect with neuroscience in the tumor microenvironment Cancer Cell 2023 41 3 573 580 10.1016/j.ccell.2023.02.012 36917953 PMC10202656 Hanahan D, Monje M. Cancer hallmarks intersect with neuroscience in the tumor microenvironment. Cancer Cell. 2023;41(3):573–80. 36917953 10.1016/j.ccell.2023.02.012 PMC10202656

154. Cervantes-Villagrana RD Albores-García D Cervantes-Villagrana AR Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies Signal Transduct Target Ther 2020 5 1 99 10.1038/s41392-020-0205-z 32555170 PMC7303203 Cervantes-Villagrana RD, Albores-García D, Cervantes-Villagrana AR, et al. Tumor-induced neurogenesis and immune evasion as targets of innovative anti-cancer therapies. Signal Transduct Target Ther. 2020;5(1):99. 32555170 10.1038/s41392-020-0205-z PMC7303203

155. Nakagawara A Trk receptor tyrosine kinases: a bridge between cancer and neural development Cancer Lett 2001 169 2 107 114 10.1016/S0304-3835(01)00530-4 11431098 Nakagawara A. Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett. 2001;169(2):107–14. 11431098 10.1016/s0304-3835(01)00530-4

156. Li M Zhou H Yang C Bacterial outer membrane vesicles as a platform for biomedical applications: an update J Control Release 2020 323 253 268 10.1016/j.jconrel.2020.04.031 32333919 Li M, Zhou H, Yang C, et al. Bacterial outer membrane vesicles as a platform for biomedical applications: an update. J Control Release. 2020;323:253–68. 32333919 10.1016/j.jconrel.2020.04.031

157. Qin J, Liu J, Wei Z, et al. Targeted intervention in nerve–cancer crosstalk enhances pancreatic cancer chemotherapy.1–14. 10.1038/s41565-024-01803-1 39496914

158. Liu H Zhu X Wei Y Recent advances in targeted gene silencing and cancer therapy by nanoparticle-based delivery systems Biomed Pharmacother 2023 157 114065 10.1016/j.biopha.2022.114065 36481408 Liu H, Zhu X, Wei Y, et al. Recent advances in targeted gene silencing and cancer therapy by nanoparticle-based delivery systems. Biomed Pharmacother. 2023;157: 114065. 36481408 10.1016/j.biopha.2022.114065

159. Gujrati M Vaidya AM Mack M Targeted dual pH-sensitive lipid ECO/siRNA self-assembly nanoparticles facilitate in vivo cytosolic sieIF4E delivery and overcome paclitaxel resistance in breast cancer therapy Adv Healthc Mater 2016 5 22 2882 2895 10.1002/adhm.201600677 27723260 PMC5589336 Gujrati M, Vaidya AM, Mack M, et al. Targeted dual pH-sensitive lipid ECO/siRNA self-assembly nanoparticles facilitate in vivo cytosolic sieIF4E delivery and overcome paclitaxel resistance in breast cancer therapy. Adv Healthc Mater. 2016;5(22):2882–95. 27723260 10.1002/adhm.201600677 PMC5589336

160. Tang Q Liu J Jiang Y Cell-selective messenger RNA delivery and CRISPR/Cas9 genome editing by modulating the interface of phenylboronic acid-derived lipid nanoparticles and cellular surface sialic acid ACS Appl Mater Interfaces 2019 11 50 46585 46590 10.1021/acsami.9b17749 31763806 Tang Q, Liu J, Jiang Y, et al. Cell-selective messenger RNA delivery and CRISPR/Cas9 genome editing by modulating the interface of phenylboronic acid-derived lipid nanoparticles and cellular surface sialic acid. ACS Appl Mater Interfaces. 2019;11(50):46585–90. 31763806 10.1021/acsami.9b17749

161. Chen Z Xiong M Tian J Encapsulation and assessment of therapeutic cargo in engineered exosomes: a systematic review J Nanobiotechnol 2024 22 1 18 10.1186/s12951-023-02259-6 PMC10765779 38172932 Chen Z, Xiong M, Tian J, et al. Encapsulation and assessment of therapeutic cargo in engineered exosomes: a systematic review. J Nanobiotechnol. 2024;22(1):18. 10.1186/s12951-023-02259-6 PMC10765779 38172932

162. Cheng Z Li M Dey R Nanomaterials for cancer therapy: current progress and perspectives J Hematol Oncol 2021 14 1 85 10.1186/s13045-021-01096-0 34059100 PMC8165984 Cheng Z, Li M, Dey R, et al. Nanomaterials for cancer therapy: current progress and perspectives. J Hematol Oncol. 2021;14(1):85. 34059100 10.1186/s13045-021-01096-0 PMC8165984

163. Hadla M Palazzolo S Corona G Exosomes increase the therapeutic index of doxorubicin in breast and ovarian cancer mouse models Nanomedicine 2016 11 18 2431 2441 10.2217/nnm-2016-0154 27558906 Hadla M, Palazzolo S, Corona G, et al. Exosomes increase the therapeutic index of doxorubicin in breast and ovarian cancer mouse models. Nanomedicine. 2016;11(18):2431–41. 27558906 10.2217/nnm-2016-0154

164. Zhuo Y Luo Z Zhu Z Direct cytosolic delivery of siRNA via cell membrane fusion using cholesterol-enriched exosomes Nat Nanotechnol 2024 19 12 1858 1868 10.1038/s41565-024-01785-0 39300226 Zhuo Y, Luo Z, Zhu Z, et al. Direct cytosolic delivery of siRNA via cell membrane fusion using cholesterol-enriched exosomes. Nat Nanotechnol. 2024;19(12):1858–68. 39300226 10.1038/s41565-024-01785-0

165. Osaki T Yokoe I Sunden Y Efficacy of 5-aminolevulinic acid in photodynamic detection and photodynamic therapy in veterinary medicine Cancers 2019 11 4 5 10.3390/cancers11040495 PMC6520946 30959982 Osaki T, Yokoe I, Sunden Y, et al. Efficacy of 5-aminolevulinic acid in photodynamic detection and photodynamic therapy in veterinary medicine. Cancers. 2019;11(4):5. 10.3390/cancers11040495 PMC6520946 30959982

166. Zhuo X Liu Z Aishajiang R Recent progress of copper-based nanomaterials in tumor-targeted photothermal therapy/photodynamic therapy Pharmaceutics 2023 15 9 1 10.3390/pharmaceutics15092293 PMC10534922 37765262 Zhuo X, Liu Z, Aishajiang R, et al. Recent progress of copper-based nanomaterials in tumor-targeted photothermal therapy/photodynamic therapy. Pharmaceutics. 2023;15(9):1. 10.3390/pharmaceutics15092293 PMC10534922 37765262

167. Qin L Yan P Xie C Gold nanorod-assembled ZnGa(2)O(4): Cr nanofibers for LED-amplified gene silencing in cancer cells Nanoscale 2018 10 28 13432 13442 10.1039/C8NR03802C 29972189 Qin L, Yan P, Xie C, et al. Gold nanorod-assembled ZnGa(2)O(4): Cr nanofibers for LED-amplified gene silencing in cancer cells. Nanoscale. 2018;10(28):13432–42. 29972189 10.1039/c8nr03802c

168. Franskevych D Prylutska S Grynyuk I Mode of photoexcited C(60) fullerene involvement in potentiating cisplatin toxicity against drug-resistant L1210 cells Bioimpacts 2019 9 4 211 217 10.15171/bi.2019.26 31799157 PMC6879712 Franskevych D, Prylutska S, Grynyuk I, et al. Mode of photoexcited C(60) fullerene involvement in potentiating cisplatin toxicity against drug-resistant L1210 cells. Bioimpacts. 2019;9(4):211–7. 31799157 10.15171/bi.2019.26 PMC6879712

169. Grebinyk A Prylutska S Chepurna O Synergy of chemo- and photodynamic therapies with C(60) fullerene-doxorubicin nanocomplex Nanomaterials 2019 9 11 1 10.3390/nano9111540 PMC6915635 31671590 Grebinyk A, Prylutska S, Chepurna O, et al. Synergy of chemo- and photodynamic therapies with C(60) fullerene-doxorubicin nanocomplex. Nanomaterials. 2019;9(11):1. 10.3390/nano9111540 PMC6915635 31671590

170. Liu J Zhu C Xu L Nanoenabled intracellular calcium bursting for safe and efficient reversal of drug resistance in tumor cells Nano Lett 2020 20 11 8102 8111 10.1021/acs.nanolett.0c03042 33064007 Liu J, Zhu C, Xu L, et al. Nanoenabled intracellular calcium bursting for safe and efficient reversal of drug resistance in tumor cells. Nano Lett. 2020;20(11):8102–11. 33064007 10.1021/acs.nanolett.0c03042

171. Higgins CF Multiple molecular mechanisms for multidrug resistance transporters Nature 2007 446 7137 749 757 10.1038/nature05630 17429392 Higgins CF. Multiple molecular mechanisms for multidrug resistance transporters. Nature. 2007;446(7137):749–57. 17429392 10.1038/nature05630

172. Zou J Xing X Teng C Cocrystal@protein-anchoring nanococktail for combinatorially treating multidrug-resistant cancer Acta Pharm Sin B 2024 14 10 4509 4525 10.1016/j.apsb.2024.08.014 39525582 PMC11544293 Zou J, Xing X, Teng C, et al. Cocrystal@protein-anchoring nanococktail for combinatorially treating multidrug-resistant cancer. Acta Pharm Sin B. 2024;14(10):4509–25. 39525582 10.1016/j.apsb.2024.08.014 PMC11544293

173. Patel NR Pattni BS Abouzeid AH Nanopreparations to overcome multidrug resistance in cancer Adv Drug Deliv Rev 2013 65 13–14 1748 1762 10.1016/j.addr.2013.08.004 23973912 PMC3840079 Patel NR, Pattni BS, Abouzeid AH, et al. Nanopreparations to overcome multidrug resistance in cancer. Adv Drug Deliv Rev. 2013;65(13–14):1748–62. 23973912 10.1016/j.addr.2013.08.004 PMC3840079

174. Zheng Y Su C Zhao L mAb MDR1-modified chitosan nanoparticles overcome acquired EGFR-TKI resistance through two potential therapeutic targets modulation of MDR1 and autophagy J Nanobiotechnol 2017 15 1 66 10.1186/s12951-017-0302-5 PMC5628454 28978341 Zheng Y, Su C, Zhao L, et al. mAb MDR1-modified chitosan nanoparticles overcome acquired EGFR-TKI resistance through two potential therapeutic targets modulation of MDR1 and autophagy. J Nanobiotechnol. 2017;15(1):66. 10.1186/s12951-017-0302-5 PMC5628454 28978341

175. Levy JMM Towers CG Thorburn A Targeting autophagy in cancer Nat Rev Cancer 2017 17 9 528 542 10.1038/nrc.2017.53 28751651 PMC5975367 Levy JMM, Towers CG, Thorburn A. Targeting autophagy in cancer. Nat Rev Cancer. 2017;17(9):528–42. 28751651 10.1038/nrc.2017.53 PMC5975367

176. Ma Z Lin K Tang M A pH-driven small-molecule nanotransformer hijacks lysosomes and overcomes autophagy-induced resistance in cancer Angew Chem Int Ed Engl 2022 61 35 e202204567 10.1002/anie.202204567 35791769 PMC9995155 Ma Z, Lin K, Tang M, et al. A pH-driven small-molecule nanotransformer hijacks lysosomes and overcomes autophagy-induced resistance in cancer. Angew Chem Int Ed Engl. 2022;61(35): e202204567. 35791769 10.1002/anie.202204567 PMC9995155

177. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med. 2017;5(9) : 691–706. 10.1016/S2213-2600(17)30293-X PMC5573769 28822787

178. Forest V Pourchez J Nano-delivery to the lung - by inhalation or other routes and why nano when micro is largely sufficient? Adv Drug Deliv Rev 2022 183 114173 10.1016/j.addr.2022.114173 35217112 Forest V, Pourchez J. Nano-delivery to the lung - by inhalation or other routes and why nano when micro is largely sufficient? Adv Drug Deliv Rev. 2022;183: 114173. 35217112 10.1016/j.addr.2022.114173

179. Zhou QT Leung SS Tang P Inhaled formulations and pulmonary drug delivery systems for respiratory infections Adv Drug Deliv Rev 2015 85 83 99 10.1016/j.addr.2014.10.022 25451137 Zhou QT, Leung SS, Tang P, et al. Inhaled formulations and pulmonary drug delivery systems for respiratory infections. Adv Drug Deliv Rev. 2015;85:83–99. 25451137 10.1016/j.addr.2014.10.022

180. Jin Z Gao Q Wu K Harnessing inhaled nanoparticles to overcome the pulmonary barrier for respiratory disease therapy Adv Drug Deliv Rev 2023 202 115111 10.1016/j.addr.2023.115111 37820982 Jin Z, Gao Q, Wu K, et al. Harnessing inhaled nanoparticles to overcome the pulmonary barrier for respiratory disease therapy. Adv Drug Deliv Rev. 2023;202: 115111. 37820982 10.1016/j.addr.2023.115111

181. Ngan CL Asmawi AA Lipid-based pulmonary delivery system: a review and future considerations of formulation strategies and limitations Drug Deliv Transl Res 2018 8 5 1527 1544 10.1007/s13346-018-0550-4 29881970 Ngan CL, Asmawi AA. Lipid-based pulmonary delivery system: a review and future considerations of formulation strategies and limitations. Drug Deliv Transl Res. 2018;8(5):1527–44. 29881970 10.1007/s13346-018-0550-4

182. Joshi K Chandra A Jain K Nanocrystalization: an emerging technology to enhance the bioavailability of poorly soluble drugs Pharm Nanotechnol 2019 7 4 259 278 10.2174/2211738507666190405182524 30961518 PMC6967137 Joshi K, Chandra A, Jain K, et al. Nanocrystalization: an emerging technology to enhance the bioavailability of poorly soluble drugs. Pharm Nanotechnol. 2019;7(4):259–78. 30961518 10.2174/2211738507666190405182524 PMC6967137

183. Ahmad J Akhter S Rizwanullah M Nanotechnology-based inhalation treatments for lung cancer: state of the art Nanotechnol Sci Appl 2015 8 55 66 26640374 10.2147/NSA.S49052 PMC4657804 Ahmad J, Akhter S, Rizwanullah M, et al. Nanotechnology-based inhalation treatments for lung cancer: state of the art. Nanotechnol Sci Appl. 2015;8:55–66. 26640374 10.2147/NSA.S49052 PMC4657804

184. Peng S Wang W Zhang R Nano-formulations for pulmonary delivery: past, present, and future perspectives Pharmaceutics 2024 16 2 4 10.3390/pharmaceutics16020161 PMC10893528 38399222 Peng S, Wang W, Zhang R, et al. Nano-formulations for pulmonary delivery: past, present, and future perspectives. Pharmaceutics. 2024;16(2):4. 10.3390/pharmaceutics16020161 PMC10893528 38399222

185. Golia A, Mahmood BR, Fundora Y, et al. Amikacin Liposome Inhalation Suspension for Mycobacterium avium Complex Lung Disease. Sr Care Pharm. 2020; 35(4) : 162–70. 10.4140/TCP.n.2020.162 32192565

186. Ziaei E Emami J Rezazadeh M Pulmonary delivery of docetaxel and celecoxib by PLGA porous microparticles for their synergistic effects against lung cancer Anticancer Agents Med Chem 2022 22 5 951 967 10.2174/1871520621666210811111152 34382530 Ziaei E, Emami J, Rezazadeh M, et al. Pulmonary delivery of docetaxel and celecoxib by PLGA porous microparticles for their synergistic effects against lung cancer. Anticancer Agents Med Chem. 2022;22(5):951–67. 34382530 10.2174/1871520621666210811111152

187. Campbell NRC Ordunez P Giraldo G WHO HEARTS: a global program to reduce cardiovascular disease burden: experience implementing in the Americas and opportunities in Canada Can J Cardiol 2021 37 5 744 755 10.1016/j.cjca.2020.12.004 33310142 Campbell NRC, Ordunez P, Giraldo G, et al. WHO HEARTS: a global program to reduce cardiovascular disease burden: experience implementing in the Americas and opportunities in Canada. Can J Cardiol. 2021;37(5):744–55. 33310142 10.1016/j.cjca.2020.12.004

188. Wang H Hsu JC Song W Nanorepair medicine for treatment of organ injury Natl Sci Rev 2024 11 9 nwae280 10.1093/nsr/nwae280 39257435 PMC11384914 Wang H, Hsu JC, Song W, et al. Nanorepair medicine for treatment of organ injury. Natl Sci Rev. 2024;11(9):nwae280. 39257435 10.1093/nsr/nwae280 PMC11384914

189. Elsabahy M Heo GS Lim SM Polymeric nanostructures for imaging and therapy Chem Rev 2015 115 19 10967 11011 10.1021/acs.chemrev.5b00135 26463640 PMC4610256 Elsabahy M, Heo GS, Lim SM, et al. Polymeric nanostructures for imaging and therapy. Chem Rev. 2015;115(19):10967–1011. 26463640 10.1021/acs.chemrev.5b00135 PMC4610256

190. Weissleder R Elizondo G Wittenberg J Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging Radiology 1990 175 2 489 493 10.1148/radiology.175.2.2326474 2326474 Weissleder R, Elizondo G, Wittenberg J, et al. Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging. Radiology. 1990;175(2):489–93. 2326474 10.1148/radiology.175.2.2326474

191. Lanza GM Wallace KD Scott MJ A novel site-targeted ultrasonic contrast agent with broad biomedical application Circulation 1996 94 12 3334 3340 10.1161/01.CIR.94.12.3334 8989148 Lanza GM, Wallace KD, Scott MJ, et al. A novel site-targeted ultrasonic contrast agent with broad biomedical application. Circulation. 1996;94(12):3334–40. 8989148 10.1161/01.cir.94.12.3334

192. Lanza GM Wallace KD Fischer SE High-frequency ultrasonic detection of thrombi with a targeted contrast system Ultrasound Med Biol 1997 23 6 863 870 10.1016/S0301-5629(97)00046-X 9300990 Lanza GM, Wallace KD, Fischer SE, et al. High-frequency ultrasonic detection of thrombi with a targeted contrast system. Ultrasound Med Biol. 1997;23(6):863–70. 9300990 10.1016/s0301-5629(97)00046-x

193. Park D Cho Y Goh SH Hyaluronic acid-polypyrrole nanoparticles as pH-responsive theranostics Chem Commun 2014 50 95 15014 15017 10.1039/C4CC06349J 25327482 Park D, Cho Y, Goh SH, et al. Hyaluronic acid-polypyrrole nanoparticles as pH-responsive theranostics. Chem Commun. 2014;50(95):15014–7. 10.1039/c4cc06349j 25327482

194. Qin J Peng Z Li B Gold nanorods as a theranostic platform for in vitro and in vivo imaging and photothermal therapy of inflammatory macrophages Nanoscale 2015 7 33 13991 14001 10.1039/C5NR02521D 26228112 Qin J, Peng Z, Li B, et al. Gold nanorods as a theranostic platform for in vitro and in vivo imaging and photothermal therapy of inflammatory macrophages. Nanoscale. 2015;7(33):13991–4001. 26228112 10.1039/c5nr02521d

195. Kang S Lee HW Jeon YH Combined fluorescence and magnetic resonance imaging of primary macrophage migration to sites of acute inflammation using near-infrared fluorescent magnetic nanoparticles Mol Imaging Biol 2015 17 5 643 651 10.1007/s11307-015-0830-z 25669929 Kang S, Lee HW, Jeon YH, et al. Combined fluorescence and magnetic resonance imaging of primary macrophage migration to sites of acute inflammation using near-infrared fluorescent magnetic nanoparticles. Mol Imaging Biol. 2015;17(5):643–51. 25669929 10.1007/s11307-015-0830-z

196. Huang Y Li L Zhang D Gadolinium-doped carbon quantum dots loaded magnetite nanoparticles as a bimodal nanoprobe for both fluorescence and magnetic resonance imaging Magn Reson Imaging 2020 68 113 120 10.1016/j.mri.2020.02.003 32032662 Huang Y, Li L, Zhang D, et al. Gadolinium-doped carbon quantum dots loaded magnetite nanoparticles as a bimodal nanoprobe for both fluorescence and magnetic resonance imaging. Magn Reson Imaging. 2020;68:113–20. 32032662 10.1016/j.mri.2020.02.003

197. Bruckman MA Jiang K Simpson EJ Dual-modal magnetic resonance and fluorescence imaging of atherosclerotic plaques in vivo using VCAM-1 targeted tobacco mosaic virus Nano Lett 2014 14 3 1551 1558 10.1021/nl404816m 24499194 PMC4169141 Bruckman MA, Jiang K, Simpson EJ, et al. Dual-modal magnetic resonance and fluorescence imaging of atherosclerotic plaques in vivo using VCAM-1 targeted tobacco mosaic virus. Nano Lett. 2014;14(3):1551–8. 24499194 10.1021/nl404816m PMC4169141

198. Kwon SP Jeon S Lee SH Thrombin-activatable fluorescent peptide incorporated gold nanoparticles for dual optical/computed tomography thrombus imaging Biomaterials 2018 150 125 136 10.1016/j.biomaterials.2017.10.017 29035738 Kwon SP, Jeon S, Lee SH, et al. Thrombin-activatable fluorescent peptide incorporated gold nanoparticles for dual optical/computed tomography thrombus imaging. Biomaterials. 2018;150:125–36. 29035738 10.1016/j.biomaterials.2017.10.017

199. Wu Q Pan W Wu G CD40-targeting magnetic nanoparticles for MRI/optical dual-modality molecular imaging of vulnerable atherosclerotic plaques Atherosclerosis 2023 369 17 26 10.1016/j.atherosclerosis.2023.02.008 36863196 Wu Q, Pan W, Wu G, et al. CD40-targeting magnetic nanoparticles for MRI/optical dual-modality molecular imaging of vulnerable atherosclerotic plaques. Atherosclerosis. 2023;369:17–26. 36863196 10.1016/j.atherosclerosis.2023.02.008

200. Tao Y Lan X Zhang Y Biomimetic nanomedicines for precise atherosclerosis theranostics Acta Pharm Sin B 2023 13 11 4442 4460 10.1016/j.apsb.2022.11.014 37969739 PMC10638499 Tao Y, Lan X, Zhang Y, et al. Biomimetic nanomedicines for precise atherosclerosis theranostics. Acta Pharm Sin B. 2023;13(11):4442–60. 37969739 10.1016/j.apsb.2022.11.014 PMC10638499

201. McCarthy JR Korngold E Weissleder R A light-activated theranostic nanoagent for targeted macrophage ablation in inflammatory atherosclerosis Small 2010 6 18 2041 2049 10.1002/smll.201000596 20721949 PMC3018665 McCarthy JR, Korngold E, Weissleder R, et al. A light-activated theranostic nanoagent for targeted macrophage ablation in inflammatory atherosclerosis. Small. 2010;6(18):2041–9. 20721949 10.1002/smll.201000596 PMC3018665

202. Lobatto ME Fayad ZA Silvera S Multimodal clinical imaging to longitudinally assess a nanomedical anti-inflammatory treatment in experimental atherosclerosis Mol Pharm 2010 7 6 2020 2029 10.1021/mp100309y 21028895 PMC3345199 Lobatto ME, Fayad ZA, Silvera S, et al. Multimodal clinical imaging to longitudinally assess a nanomedical anti-inflammatory treatment in experimental atherosclerosis. Mol Pharm. 2010;7(6):2020–9. 21028895 10.1021/mp100309y PMC3345199

203. Iverson NM Plourde NM Sparks SM Dual use of amphiphilic macromolecules as cholesterol efflux triggers and inhibitors of macrophage athero-inflammation Biomaterials 2011 32 32 8319 8327 10.1016/j.biomaterials.2011.07.039 21816466 PMC3167147 Iverson NM, Plourde NM, Sparks SM, et al. Dual use of amphiphilic macromolecules as cholesterol efflux triggers and inhibitors of macrophage athero-inflammation. Biomaterials. 2011;32(32):8319–27. 21816466 10.1016/j.biomaterials.2011.07.039 PMC3167147

204. Tavares ER Freitas FR Diament J Reduction of atherosclerotic lesions in rabbits treated with etoposide associated with cholesterol-rich nanoemulsions Int J Nanomed 2011 6 2297 2304 10.2147/IJN.S24048 PMC3205126 22072867 Tavares ER, Freitas FR, Diament J, et al. Reduction of atherosclerotic lesions in rabbits treated with etoposide associated with cholesterol-rich nanoemulsions. Int J Nanomed. 2011;6:2297–304. 10.2147/IJN.S24048 PMC3205126 22072867

205. Wu Z Chen C Zhang B EGFP-EGF1-conjugated poly(lactic-co-glycolic acid) nanoparticles, a new diagnostic tool and drug carrier for atherosclerosis Int J Nanomed 2019 14 2609 2618 10.2147/IJN.S199695 PMC6469482 31043777 Wu Z, Chen C, Zhang B, et al. EGFP-EGF1-conjugated poly(lactic-co-glycolic acid) nanoparticles, a new diagnostic tool and drug carrier for atherosclerosis. Int J Nanomed. 2019;14:2609–18. 10.2147/IJN.S199695 PMC6469482 31043777

206. Zhao Y Imura T Leman LJ Mimicry of high-density lipoprotein: functional peptide-lipid nanoparticles based on multivalent peptide constructs J Am Chem Soc 2013 135 36 13414 13424 10.1021/ja404714a 23978057 PMC3839580 Zhao Y, Imura T, Leman LJ, et al. Mimicry of high-density lipoprotein: functional peptide-lipid nanoparticles based on multivalent peptide constructs. J Am Chem Soc. 2013;135(36):13414–24. 23978057 10.1021/ja404714a PMC3839580

207. Shin MD Ortega-Rivera OA Steinmetz NF Multivalent display of ApoAI peptides on the surface of tobacco mosaic virus nanotubes improves cholesterol efflux Bioconjug Chem 2022 33 10 1922 1933 10.1021/acs.bioconjchem.2c00371 36191144 PMC9772860 Shin MD, Ortega-Rivera OA, Steinmetz NF. Multivalent display of ApoAI peptides on the surface of tobacco mosaic virus nanotubes improves cholesterol efflux. Bioconjug Chem. 2022;33(10):1922–33. 36191144 10.1021/acs.bioconjchem.2c00371 PMC9772860

208. Mu D Li J Qi Y Hyaluronic acid-coated polymeric micelles with hydrogen peroxide scavenging to encapsulate statins for alleviating atherosclerosis J Nanobiotechnol 2020 18 1 179 10.1186/s12951-020-00744-w PMC7720571 33287831 Mu D, Li J, Qi Y, et al. Hyaluronic acid-coated polymeric micelles with hydrogen peroxide scavenging to encapsulate statins for alleviating atherosclerosis. J Nanobiotechnol. 2020;18(1):179. 10.1186/s12951-020-00744-w PMC7720571 33287831

209. Xie S Mo C Cao W Bacteria-propelled microtubular motors for efficient penetration and targeting delivery of thrombolytic agents Acta Biomater 2022 142 49 59 10.1016/j.actbio.2022.02.008 35158079 Xie S, Mo C, Cao W, et al. Bacteria-propelled microtubular motors for efficient penetration and targeting delivery of thrombolytic agents. Acta Biomater. 2022;142:49–59. 35158079 10.1016/j.actbio.2022.02.008

210. Xie DM Zhong Q Xu X Alpha lipoic acid-loaded electrospun fibrous patch films protect heart in acute myocardial infarction mice by inhibiting oxidative stress Int J Pharm 2023 632 122581 10.1016/j.ijpharm.2023.122581 36608806 Xie DM, Zhong Q, Xu X, et al. Alpha lipoic acid-loaded electrospun fibrous patch films protect heart in acute myocardial infarction mice by inhibiting oxidative stress. Int J Pharm. 2023;632: 122581. 36608806 10.1016/j.ijpharm.2023.122581

211. Li H Zhu J Xu YW Notoginsenoside R1-loaded mesoporous silica nanoparticles targeting the site of injury through inflammatory cells improves heart repair after myocardial infarction Redox Biol 2022 54 102384 10.1016/j.redox.2022.102384 35777198 PMC9287735 Li H, Zhu J, Xu YW, et al. Notoginsenoside R1-loaded mesoporous silica nanoparticles targeting the site of injury through inflammatory cells improves heart repair after myocardial infarction. Redox Biol. 2022;54: 102384. 35777198 10.1016/j.redox.2022.102384 PMC9287735

212. Lan M Hou M Yan J Cardiomyocyte-targeted anti-inflammatory nanotherapeutics against myocardial ischemia reperfusion (IR) injury Nano Res 2022 15 10 9125 9134 10.1007/s12274-022-4553-6 35915748 PMC9328183 Lan M, Hou M, Yan J, et al. Cardiomyocyte-targeted anti-inflammatory nanotherapeutics against myocardial ischemia reperfusion (IR) injury. Nano Res. 2022;15(10):9125–34. 35915748 10.1007/s12274-022-4553-6 PMC9328183

213. Bajaj A Rao MR Pardeshi A Nanocrystallization by evaporative antisolvent technique for solubility and bioavailability enhancement of telmisartan AAPS PharmSciTech 2012 13 4 1331 1340 10.1208/s12249-012-9860-x 23054986 PMC3513472 Bajaj A, Rao MR, Pardeshi A, et al. Nanocrystallization by evaporative antisolvent technique for solubility and bioavailability enhancement of telmisartan. AAPS PharmSciTech. 2012;13(4):1331–40. 23054986 10.1208/s12249-012-9860-x PMC3513472

214. Rachmawati H Soraya IS Kurniati NF In vitro study on antihypertensive and antihypercholesterolemic effects of a curcumin nanoemulsion Sci Pharm 2016 84 1 131 140 10.3797/scipharm.ISP.2015.05 27110504 PMC4839556 Rachmawati H, Soraya IS, Kurniati NF, et al. In vitro study on antihypertensive and antihypercholesterolemic effects of a curcumin nanoemulsion. Sci Pharm. 2016;84(1):131–40. 27110504 10.3797/scipharm.ISP.2015.05 PMC4839556

215. Southgate L Machado RD Gräf S Molecular genetic framework underlying pulmonary arterial hypertension Nat Rev Cardiol 2020 17 2 85 95 10.1038/s41569-019-0242-x 31406341 Southgate L, Machado RD, Gräf S, et al. Molecular genetic framework underlying pulmonary arterial hypertension. Nat Rev Cardiol. 2020;17(2):85–95. 31406341 10.1038/s41569-019-0242-x

216. Spiekerkoetter E Kawut SM de Jesus Perez VA New and emerging therapies for pulmonary arterial hypertension Annu Rev Med 2019 70 45 59 10.1146/annurev-med-041717-085955 30216732 PMC7735523 Spiekerkoetter E, Kawut SM, de Jesus Perez VA. New and emerging therapies for pulmonary arterial hypertension. Annu Rev Med. 2019;70:45–59. 30216732 10.1146/annurev-med-041717-085955 PMC7735523

217. Teng C Li B Lin C Targeted delivery of baicalein-p53 complex to smooth muscle cells reverses pulmonary hypertension J Control Release 2022 341 591 604 10.1016/j.jconrel.2021.12.006 34896449 Teng C, Li B, Lin C, et al. Targeted delivery of baicalein-p53 complex to smooth muscle cells reverses pulmonary hypertension. J Control Release. 2022;341:591–604. 34896449 10.1016/j.jconrel.2021.12.006

218. Vani JR Mohammadi MT Foroshani MS Polyhydroxylated fullerene nanoparticles attenuate brain infarction and oxidative stress in rat model of ischemic stroke Excli j 2016 15 378 390 27540350 10.17179/excli2016-309 PMC4983868 Vani JR, Mohammadi MT, Foroshani MS, et al. Polyhydroxylated fullerene nanoparticles attenuate brain infarction and oxidative stress in rat model of ischemic stroke. Excli j. 2016;15:378–90. 27540350 10.17179/excli2016-309 PMC4983868

219. Choudhury AA Devi RV Gestational diabetes mellitus—a metabolic and reproductive disorder Biomed Pharmacother 2021 143 112183 10.1016/j.biopha.2021.112183 34560536 Choudhury AA, Devi RV. Gestational diabetes mellitus—a metabolic and reproductive disorder. Biomed Pharmacother. 2021;143: 112183. 34560536 10.1016/j.biopha.2021.112183

220. Bolli GB Porcellati F Lucidi P The physiological basis of insulin therapy in people with diabetes mellitus Diabetes Res Clin Pract 2021 175 108839 10.1016/j.diabres.2021.108839 33930505 Bolli GB, Porcellati F, Lucidi P, et al. The physiological basis of insulin therapy in people with diabetes mellitus. Diabetes Res Clin Pract. 2021;175: 108839. 33930505 10.1016/j.diabres.2021.108839

221. Sarkar S Ekbal Kabir M Kalita J Mesoporous silica nanoparticles: drug delivery vehicles for antidiabetic molecules ChemBioChem 2023 24 7 e202200672 10.1002/cbic.202200672 36719179 Sarkar S, Ekbal Kabir M, Kalita J, et al. Mesoporous silica nanoparticles: drug delivery vehicles for antidiabetic molecules. ChemBioChem. 2023;24(7): e202200672. 36719179 10.1002/cbic.202200672

222. Li X Peng X Zoulikha M Multifunctional nanoparticle-mediated combining therapy for human diseases Signal Transduct Target Ther 2024 9 1 1 10.1038/s41392-023-01668-1 38161204 PMC10758001 Li X, Peng X, Zoulikha M, et al. Multifunctional nanoparticle-mediated combining therapy for human diseases. Signal Transduct Target Ther. 2024;9(1):1. 38161204 10.1038/s41392-023-01668-1 PMC10758001

223. Hunt NJ Lockwood GP Heffernan SJ Oral nanotherapeutic formulation of insulin with reduced episodes of hypoglycaemia Nat Nanotechnol 2024 19 4 534 544 10.1038/s41565-023-01565-2 38168926 PMC11026164 Hunt NJ, Lockwood GP, Heffernan SJ, et al. Oral nanotherapeutic formulation of insulin with reduced episodes of hypoglycaemia. Nat Nanotechnol. 2024;19(4):534–44. 38168926 10.1038/s41565-023-01565-2 PMC11026164

224. Xu B Jiang G Yu W H(2)O(2)-responsive mesoporous silica nanoparticles integrated with microneedle patches for the glucose-monitored transdermal delivery of insulin J Mater Chem B 2017 5 41 8200 8208 10.1039/C7TB02082A 32264463 Xu B, Jiang G, Yu W, et al. H(2)O(2)-responsive mesoporous silica nanoparticles integrated with microneedle patches for the glucose-monitored transdermal delivery of insulin. J Mater Chem B. 2017;5(41):8200–8. 32264463 10.1039/c7tb02082a

225. Shrestha N Araújo F Shahbazi MA Oral hypoglycaemic effect of GLP-1 and DPP4 inhibitor based nanocomposites in a diabetic animal model J Control Release 2016 232 113 119 10.1016/j.jconrel.2016.04.024 27091697 Shrestha N, Araújo F, Shahbazi MA, et al. Oral hypoglycaemic effect of GLP-1 and DPP4 inhibitor based nanocomposites in a diabetic animal model. J Control Release. 2016;232:113–9. 27091697 10.1016/j.jconrel.2016.04.024

226. Rocha S Lucas M Ribeiro D Nano-based drug delivery systems used as vehicles to enhance polyphenols therapeutic effect for diabetes mellitus treatment Pharmacol Res 2021 169 105604 10.1016/j.phrs.2021.105604 33845125 Rocha S, Lucas M, Ribeiro D, et al. Nano-based drug delivery systems used as vehicles to enhance polyphenols therapeutic effect for diabetes mellitus treatment. Pharmacol Res. 2021;169: 105604. 33845125 10.1016/j.phrs.2021.105604

227. Zhang J Zhou J Zhang T Facile fabrication of an amentoflavone-loaded micelle system for oral delivery to improve bioavailability and hypoglycemic effects in KKAy mice ACS Appl Mater Interfaces 2019 11 13 12904 12913 10.1021/acsami.9b03275 30860811 Zhang J, Zhou J, Zhang T, et al. Facile fabrication of an amentoflavone-loaded micelle system for oral delivery to improve bioavailability and hypoglycemic effects in KKAy mice. ACS Appl Mater Interfaces. 2019;11(13):12904–13. 30860811 10.1021/acsami.9b03275

228. Chen H Khemtong C Yang X Nanonization strategies for poorly water-soluble drugs Drug Discovery Today 2011 16 7 354 360 10.1016/j.drudis.2010.02.009 20206289 Chen H, Khemtong C, Yang X, et al. Nanonization strategies for poorly water-soluble drugs. Drug Discovery Today. 2011;16(7):354–60. 20206289 10.1016/j.drudis.2010.02.009

229. Goyal R Macri LK Kaplan HM Nanoparticles and nanofibers for topical drug delivery J Control Release 2016 240 77 92 10.1016/j.jconrel.2015.10.049 26518723 PMC4896846 Goyal R, Macri LK, Kaplan HM, et al. Nanoparticles and nanofibers for topical drug delivery. J Control Release. 2016;240:77–92. 26518723 10.1016/j.jconrel.2015.10.049 PMC4896846

230. Güngör S Kahraman E Nanocarriers mediated cutaneous drug delivery Eur J Pharm Sci 2021 158 105638 10.1016/j.ejps.2020.105638 33176190 Güngör S, Kahraman E. Nanocarriers mediated cutaneous drug delivery. Eur J Pharm Sci. 2021;158: 105638. 33176190 10.1016/j.ejps.2020.105638

231. Ren J Liu T Bi B Development and evaluation of tacrolimus loaded nano-transferosomes for skin targeting and dermatitis treatment J Pharm Sci 2024 113 2 471 485 10.1016/j.xphs.2023.10.033 37898166 Ren J, Liu T, Bi B, et al. Development and evaluation of tacrolimus loaded nano-transferosomes for skin targeting and dermatitis treatment. J Pharm Sci. 2024;113(2):471–85. 37898166 10.1016/j.xphs.2023.10.033

232. Fratoddi I Benassi L Botti E Effects of topical methotrexate loaded gold nanoparticle in cutaneous inflammatory mouse model Nanomedicine 2019 17 276 286 10.1016/j.nano.2019.01.006 30708054 Fratoddi I, Benassi L, Botti E, et al. Effects of topical methotrexate loaded gold nanoparticle in cutaneous inflammatory mouse model. Nanomedicine. 2019;17:276–86. 30708054 10.1016/j.nano.2019.01.006

233. Moazeni M Kelidari HR Saeedi M Time to overcome fluconazole resistant Candida isolates: solid lipid nanoparticles as a novel antifungal drug delivery system Colloids Surf B Biointerfaces 2016 142 400 407 10.1016/j.colsurfb.2016.03.013 26974361 Moazeni M, Kelidari HR, Saeedi M, et al. Time to overcome fluconazole resistant Candida isolates: solid lipid nanoparticles as a novel antifungal drug delivery system. Colloids Surf B Biointerfaces. 2016;142:400–7. 26974361 10.1016/j.colsurfb.2016.03.013

234. Dong P Sahle FF Lohan SB pH-sensitive Eudragit® L 100 nanoparticles promote cutaneous penetration and drug release on the skin J Control Release 2019 295 214 222 10.1016/j.jconrel.2018.12.045 30597246 Dong P, Sahle FF, Lohan SB, et al. pH-sensitive Eudragit® L 100 nanoparticles promote cutaneous penetration and drug release on the skin. J Control Release. 2019;295:214–22. 30597246 10.1016/j.jconrel.2018.12.045

235. Xiao Q Lu Y Yao W Molybdenum nanoparticles as a potential topical medication for alopecia treatment through antioxidant pathways that differ from minoxidil J Trace Elem Med Biol 2024 82 127368 10.1016/j.jtemb.2023.127368 38150949 Xiao Q, Lu Y, Yao W, et al. Molybdenum nanoparticles as a potential topical medication for alopecia treatment through antioxidant pathways that differ from minoxidil. J Trace Elem Med Biol. 2024;82: 127368. 38150949 10.1016/j.jtemb.2023.127368

236. Taylor AW Ocular immune privilege Eye 2009 23 10 1885 1889 10.1038/eye.2008.382 19136922 PMC4698145 Taylor AW. Ocular immune privilege. Eye. 2009;23(10):1885–9. 19136922 10.1038/eye.2008.382 PMC4698145

237. Gaudana R Ananthula HK Parenky A Ocular drug delivery Aaps j 2010 12 3 348 360 10.1208/s12248-010-9183-3 20437123 PMC2895432 Gaudana R, Ananthula HK, Parenky A, et al. Ocular drug delivery. Aaps j. 2010;12(3):348–60. 20437123 10.1208/s12248-010-9183-3 PMC2895432

238. Chakraborty M Banerjee D Mukherjee S Exploring the advancement of polymer-based nano-formulations for ocular drug delivery systems: an explicative review Polym Bull 2023 80 11759 11777 10.1007/s00289-022-04661-w Chakraborty M, Banerjee D, Mukherjee S, et al. Exploring the advancement of polymer-based nano-formulations for ocular drug delivery systems: an explicative review. Polym Bull. 2023;80:11759–77.

239. Li K Lin M Huang K Therapeutic effect and mechanism of action of pterostilbene nano drugs in dry eye models Exp Eye Res 2024 241 109836 10.1016/j.exer.2024.109836 38387712 Li K, Lin M, Huang K, et al. Therapeutic effect and mechanism of action of pterostilbene nano drugs in dry eye models. Exp Eye Res. 2024;241: 109836. 38387712 10.1016/j.exer.2024.109836

240. Cui W Chen S Hu T Nanoceria-mediated cyclosporin a delivery for dry eye disease management through modulating immune-epithelial crosstalk ACS Nano 2024 18 17 11084 11102 10.1021/acsnano.3c11514 38632691 Cui W, Chen S, Hu T, et al. Nanoceria-mediated cyclosporin a delivery for dry eye disease management through modulating immune-epithelial crosstalk. ACS Nano. 2024;18(17):11084–102. 38632691 10.1021/acsnano.3c11514

241. Hakim A Guido B Narsineni L Gene therapy strategies for glaucoma from IOP reduction to retinal neuroprotection: progress towards non-viral systems Adv Drug Deliv Rev 2023 196 114781 10.1016/j.addr.2023.114781 36940751 Hakim A, Guido B, Narsineni L, et al. Gene therapy strategies for glaucoma from IOP reduction to retinal neuroprotection: progress towards non-viral systems. Adv Drug Deliv Rev. 2023;196: 114781. 36940751 10.1016/j.addr.2023.114781

242. Zhou X Rong R Liang G Self-assembly hypoxic and ROS dual response nano prodrug as a new therapeutic approach for glaucoma treatments Adv Sci 2024 11 41 e2407043 10.1002/advs.202407043 PMC11538650 39229928 Zhou X, Rong R, Liang G, et al. Self-assembly hypoxic and ROS dual response nano prodrug as a new therapeutic approach for glaucoma treatments. Adv Sci. 2024;11(41): e2407043. 10.1002/advs.202407043 PMC11538650 39229928

243. Maulvi FA Desai DT Shetty KH Advances and challenges in the nanoparticles-laden contact lenses for ocular drug delivery Int J Pharm 2021 608 121090 10.1016/j.ijpharm.2021.121090 34530102 Maulvi FA, Desai DT, Shetty KH, et al. Advances and challenges in the nanoparticles-laden contact lenses for ocular drug delivery. Int J Pharm. 2021;608: 121090. 34530102 10.1016/j.ijpharm.2021.121090

244. Maulvi FA Soni PD Patel PJ Controlled bimatoprost release from graphene oxide laden contact lenses: In vitro and in vivo studies Colloids Surf B Biointerfaces 2021 208 112096 10.1016/j.colsurfb.2021.112096 34530331 Maulvi FA, Soni PD, Patel PJ, et al. Controlled bimatoprost release from graphene oxide laden contact lenses: In vitro and in vivo studies. Colloids Surf B Biointerfaces. 2021;208: 112096. 34530331 10.1016/j.colsurfb.2021.112096

245. Ando H Abu Lila AS Kawanishi M Reactivity of IgM antibodies elicited by PEGylated liposomes or PEGylated lipoplexes against auto and foreign antigens J Control Release 2018 270 114 119 10.1016/j.jconrel.2017.12.002 29217175 Ando H, Abu Lila AS, Kawanishi M, et al. Reactivity of IgM antibodies elicited by PEGylated liposomes or PEGylated lipoplexes against auto and foreign antigens. J Control Release. 2018;270:114–9. 29217175 10.1016/j.jconrel.2017.12.002

246. Berndt A Lee SY Ramakrishnan C Structure-guided transformation of channelrhodopsin into a light-activated chloride channel Science 2014 344 6182 420 424 10.1126/science.1252367 24763591 PMC4096039 Berndt A, Lee SY, Ramakrishnan C, et al. Structure-guided transformation of channelrhodopsin into a light-activated chloride channel. Science. 2014;344(6182):420–4. 24763591 10.1126/science.1252367 PMC4096039

247. Zhou Y Cai G Wang Y Microarray chip-based high-throughput screening of neurofilament light chain self-assembling peptide for noninvasive monitoring of Alzheimer’s disease ACS Nano 2024 18 28 18160 18175 10.1021/acsnano.3c09642 38940834 Zhou Y, Cai G, Wang Y, et al. Microarray chip-based high-throughput screening of neurofilament light chain self-assembling peptide for noninvasive monitoring of Alzheimer’s disease. ACS Nano. 2024;18(28):18160–75. 38940834 10.1021/acsnano.3c09642

248. Witten J Raji I Manan RS Artificial intelligence-guided design of lipid nanoparticles for pulmonary gene therapy Nat Biotechnol 2024 10.1038/s41587-024-02490-y 39658727 PMC12149338 Witten J, Raji I, Manan RS, et al. Artificial intelligence-guided design of lipid nanoparticles for pulmonary gene therapy. Nat Biotechnol. 2024. 10.1038/s41587-024-02490-y. 39658727 10.1038/s41587-024-02490-y PMC12149338