Organelle-oriented nanomedicines in tumor therapy: Targeting, escaping, or collaborating?

Introduction

Precision therapy represents an efficient and straightforward approach to antitumor treatment, grounded in significant advancements in oncology. Its efficacy hinges upon a range of different parameters, including the patients’ genetic profile, personal lifestyle habits, as well as pertinent environmental factors [ 1 ]. Compared to more traditional treatments, such as chemotherapy, radiotherapy, and surgery, precision therapy possesses some notable advantages: drug delivery is precise, targeted allopathic therapy can be achieved based on molecular mechanisms, and treatment options can be personalized [ 2 , 3 ].

With the in-depth exploration of tumor pathogenesis, precision therapy can precisely identify the targets that drive tumorigenesis, thus fulfilling the objective of finding allopathic treatments to address tumor heterogeneity [ 4 ]. Secondly, in light of the burgeoning array of potential therapeutic targets, optimized drug delivery schemes can be devised for precision therapy that are tailored to specific accessible targets. This creates high-quality therapies that can be tailored to specific individuals [ 2 , 5 ]. This approach significantly enhances the efficacy of the treatment and mitigates its side effects. It can also address the problem of drug resistance in tumor therapy [ 5 ]. More importantly, the growing wealth of data that has become available on genes, molecules, individuals, and environmental factors in recent years has facilitated the development of “big data” models. These models can effectively integrate precision therapy with personalized treatment plans, which offers certain advantages in chronic disease management that are often lacking in traditional treatment methods [ 6 ].

Since the inception of the concept of precision oncology (in 2003), numerous strategies focusing on the core principles of precision therapy have been proposed [ 6 , 7 ]. Most notably, the concept of organelle targeting has attracted widespread attention. Organelle-targeting therapy aims to eradicate tumors by capitalizing on the high sensitivity of specific organelles and the precision with which such targets can be attacked [ 8 , 9 ]. This capability endows organelle-targeting drugs with unique advantages: it increases delivery efficiency, enhances their treatment efficacy, reverses multidrug resistance (MDR), and mitigates toxic side effects [ [10] , [11] , [12] ]. However, a fundamental challenge arises when designing organelle-targeting nanodrugs. Organelles range in size from 10 nm to 10 μm (compared to cells that lie in the range of 10–20 μm), which means that nanomaterials could be considered the most promising carriers for designing organelle-targeting drugs [ 13 ]. Fortunately, over the past few decades, nanotechnology has witnessed some significant developments, which have led to the emergence of various nanodrug carriers [ [14] , [15] , [16] ].

On the one hand, nanomaterials require specific functionalities to approach and target particular organelles, which necessitates certain modifications in both their physical and chemical properties ( Fig. 1 a) [ 17 , 18 ]. On the other hand, the design of nanodrugs must consider the multiple barriers that they need to seamlessly overcome in order to reach their targets [ 19 , 20 ]. Furthermore, the nanodrugs must exert specific therapeutic effects, such as initiating cell apoptosis through damage pathways or releasing specific drugs to induce a therapeutic response. Concurrently integrating multiple functions represents a new direction in the ongoing advancement of nanomaterials [ 14 , 21 ]. Fig. 1 Schematic illustration of organelle-targeting nanodrug research. (a) Classification of organelle-oriented nanostructures for precise tumor therapy. (b) Proportion of research articles published on nanodrugs targeting different organelles (mitochondria, nuclei, lysosomes, endoplasmic reticulum, Golgi apparatus, and proteasomes). Data were sourced from a systematic search of the PubMed and Web of Science databases using a sampling survey approach. (Created with BioRender.com.) Fig. 1

In recent years, researchers have made various advancements to enhance the structural design of materials focusing on the relationship between composition and effect, precision of the delivery process, and maximizing efficiency [ 22 ]. Fig. 1 b highlights the classification of the research articles published to date on organelle-targeting nanodrugs. There has been a notable increase in research activity in this field over the past few decades (thus highlighting the need for them to be summarized). Nowadays, the contemporary reviews of organelle-targeting nanomedicines tend to primarily focus on individual organelles [ 23 , 24 ]. This is, of course, conducive to the design of specific nanodrugs. However, this approach has significant limitations. It is well-established that collaborative interactions occur among the various organelles that are essential for the maintenance of cellular function [ 25 , 26 ]. This understanding suggests it is important to adopt a more holistic perspective when designing organelle-targeting nanomedicines for tumor therapy. A prime example of this is evident in the design of antitumor nanodrugs that target mitochondria or nucleus, wherein overlooking the degradability of the nanodrug by lysosome often results in unsatisfactory therapeutic targeting effects [ 27 , 28 ]. On the other hand, by recognizing the collaborative roles of various organelles in tumorigenesis, nanodrugs that target multiple organelles can be developed and often yield superior therapeutic effects [ 21 , 29 ]. Hence, it is imperative to encapsulate the current developmental state of organelle-targeting nanomedicines from a broader perspective and delineate future research directions.

This review centers on the design of organelle-oriented nanodrugs and emphasizes the targeting, escaping, and collaborative roles of multiple organelles from a comprehensive perspective within the guidance of oncology ( Fig. 2 ). By collating previous research findings, we underscore the significance of adopting a holistic perspective in the design of organelle-oriented nanodrugs. Furthermore, unlike most of the previous reviews, this review begins with a thorough theoretical framework for organelle function [ 30 ]. We thus elucidate the functional interaction between the various organelles and establish a global perspective. Additionally, our review delves into the details of specific organelles. The composition-effect relationship between the structure of the nanomaterials and the nanodrugs’ targeting function is thus examined. This can help guide scientists in discovering potential organelle targeting strategies to improve precision therapy from a biological standpoint. It can also enhance the efficiency of the nanodrug design process from a broader perspective. Finally, this review also highlights some common issues in the current research. These span a wide range of subjects (biology, materials science, and clinical applications), thus indicating that there is still an extensive journey to be traversed from the current state of research to the routine clinical application of these nanodrugs. Fig. 2 Schematic illustration of organelle-oriented nanomedicines employing targeting (a), escaping (b) and collaborating (c) strategies in precise tumor therapy. (Created with BioRender.com.) Fig. 2

Nanostructure design for organelle targeting

In eukaryotic cells, there are three primary structures: the nucleus, cell membrane (CM), and cytoplasm [ 31 , 32 ]. In turn, the cytoplasm contains a wide variety of subcellular organelles and a large number of inclusions. Typical organelles include mitochondria, lysosomes, endoplasmic reticulum (ER), Golgi apparatus (GA), and peroxisomes, etc . [ 33 , 34 ]. Each subcellular component plays specialized roles to support the fundamental functions of the cell and maintain biological homeostasis [ 35 ]. As each subcellular compartment is crucial to the proper functioning of the cell, it stands to reason that interfering with, or destroying, any one of them could induce cell death in an essential manner. This suggestion sheds light on the promising field of tumor treatment by focusing on the subcellular organelles. Armed with an understanding of the distinct functions of the organelle structures, it should be possible to design advanced drug delivery systems (DDSs) to precisely target the specialized organelles of tumor cells. This can obviously lead to a more effective approach to precision medicine ( Fig. 3 ). This refined approach to drug delivery is certain to lead to treatments with significantly enhanced efficacy ( Table 1 ). Fig. 3 Schematic illustration of organelle targeting nanodrugs in precise tumor therapy. (Created with BioRender.com.) Fig. 3 Table 1 Summary of recent articles on organelle targeting in precise tumor therapy. Table 1 Organelle Mechanism of action Form Structure Preparation and functionalization Diameter (nm) Cell lines Animal model Therapy Ref. Mitochondrion Mitochondrion-targeting agents Delocalized lipophilic cations Nanocomposites AIBI@H-mMnO 2 -TPP@PDA-RGD, AHTPR EA, HI, CC, RR a 370.0 Human OS (MNNG/HOS) Subcutaneous OS xenograft PTT; Thermodynamic therapy [ 48 ] Transition metal complexes Nanorods Au@SiO 2 -SNO/PEG/TPP; GSNP-TPP CC, EA, PE 110 HeLa HeLa tumor-bearing mice PTT [ 63 ] Mitochondrion- Permeable peptides Nanoparticles miR-200/omSLN-CMN; Iri/omLip-CMN EA, HI, PE, CC, BF 148.6 ± 0.36 175.2 ± 2.27 HNC SAS SAS tumor-bearing mice Chemotherapy; Gene therapy [ 66 ] mtDNA perturbation Herpesvirus-mimicking nanoparticles Vir-ZM@TD PE, CC, CI, BF 160 4T1 4T1-tumor-bearing mice Immunotherapy [ 72 ] Nanoflowers mtDNA mutation-induced drug release system EA, HGI, BF, GEF ∼300 B16 HK2 HCT 116 RAW 264.7 NCTC 1469 HEK 293T B16/RAW 264.7 cell tumor-bearing mice PDT [ 76 ] Metabolism disruption Substancemetabolism inhibition Nanosheets FX11@TPEG-WS 2 CC, VDW, BF ∼100 MCF-7 MCF-7 tumor-bearing mice Piezodynamic therapy; Chemotherapy [ 90 ] Energy metabolism interference Nanoplatforms α-CD-DOX-NO-DA CC, HGI 195.3 (PDI 0.194); 203.6 (PDI 0.270) MCF-7 4T1 MCF-7/DOX tumor-bearing nude mice; MCF-7/DOX orthotopic 4T1 tumor model Chemotherapy [ 95 ] DNA Nanostructures TDNs-G-TPP CC, CI, BF 10.1 ± 3.4 MCF-7 NA NA [ 98 ] Redox state imbalance Nanovesicles PEBP-VES-D-Ps VDW, HI, PE 135.9 MCF-7 MCF-7/ADR K562 K562/ADR K562/ADR tumor-bearing nude mice Chemotherapy [ 265 ] Mitochondrion-associated protein modulation Nanoplatforms Au@MSN-Cu/PEG/DSF CC, PE, CI 195.38 (in H 2 O); 221.81 (in DMEM with 10 % FBS) 4T1 4T1 subcutaneous tumor-bearing mice PTT [ 110 ] Nucleus Nucleus-targeting agents Nuclear localization signal modification Nanocapsules BSNPs PE, CC, BF 67.5 HeLa HeLa-tumor-bearing nude mice Antitumor protein therapy [ 123 ] Transactivator of transcription peptides Nanoparticle CD133/TAT/TPZ-Fe 3 O 4 @mSiO 2 PE, CC, BF 91.6 MCF-7 BCSCs tumor-bearing nude mice Chemotherapy [ 129 ] Nuclear envelope integrity impairment Nanoparticles; Vapor nanobubbles AuNPs NA 70 HeLa NA Chemotherapy [ 138 ] Nuclear DNA perturbation Nanocrystals Ir-RGD-TAT (Ir-R/T) CC, RR, BF ∼4 4T1 Mammary 4T1 tumor-bearing female nude mice Photonic hyperthermia-synergized radiotherapy [ 128 ] Nanodrug delivery system CBNs-Pluronic F127-DOX VDW, PE CBNs: 3 - 5 CPD: 68 4T1 BALB/c mice Chemotherapy [ 142 ] Lysosome Lysosome-targeting agents Lysosomal sorting peptides Nanoparticles YQRLGC-conjugated MSNs EA, PE, CC, BF ∼200 HeLa NA Chemotherapy [ 165 ] Lysosome membrane permeabilization induction Nanocomposites LDH-CuS NCs CI 20.02 ± 4.28 4T1 4T1 tumor-bearing mice PDT; CDT [ 172 ] Lysosome-dependent cell death Ferroptosis Nanodots Cu NDs EA, CI 6.5 Cal-27 HNSCC xenograft mice; HNSCC PDX mice Chemotherapy [ 191 ] Pyroptosis Self-assembled nanoparticles (Nig + DAC)@HmA PE, CI 218.4 ± 3.2 MB49 4T1 MB49 tumor-bearing mice Immunotherapy [ 266 ] Endoplasmic reticulum Endoplasmic reticulum-targeting agents ER retrieval signal Nanoconstructs AuNP-KDEL CC, CI, BF 20 Sol8 myogenic NA Chemotherapy [ 202 ] Endoplasmic reticulum stress Abnormal protein folding Nanomedicine GCT@CM NPs HI, CI, BF 210 B16 L929 RAW 264.7 B16-tumor-bearing mice Chemotherapy [ 210 ] Calcium homeostasis imbalance Nanoplatform UCNPs-Ce6@RuR@mSiO 2 @PL-HA NPs; CaO 2 @HASA NPs EA, PE, CC, BF 64.7 ± 0.2 4T1 4T1 tumor-bearing mice PDT [ 213 ] Immunogenic cell death Nanoparticles NPER/BO-PDT HI, CC, CIHI ∼100 K7M2 K7M2 tumor bearing mice PDT; immunotherapy [ 214 ] Endoplasmic reticulum-associated immune regulation Nanovaccine A mixture of an antigen and polymeric nanoparticles HI, PE 29 THP-1 B16-OVA TC-1 MC38 C57BL/6 mice; INF-α/βR −/− mice; STING gt/gt mice; MyD88 −/− mice; TRIF −/− mice; OT-1 mice; C57BL/6-CD45.1 mice Immunotherapy [ 226 ] Golgi apparatus Golgi apparatus-targeting agents Chondroitin sulfate Nanoformulation PTX-CS-RA HI, PE, CC 192.7 ± 1.8 4T1 4T1-luc bearing mice Chemotherapy [ 235 ] Golgi apparatus-mediated endocytosis Nanoparticles MTC/TPP NPs EA, PE, BF, GEF NA RAW 264.7 syntaxin6 −/− and NPC1 −/− mice Gene therapy [ 267 ] Golgi apparatus-dependent cell death Nanoparticles Ag@ZnO RR, CI 70 A375 normal dermal fibroblasts NA PDT [ 247 ] Proteasome Proteasome-targeting agents Proteolysis-targeting chimeras Nano-PROTACs nano-PROTACs HI, CC NA 4T1 4T1 tumor-bearing mice Photo-immunotherapy [ 268 ] Nanoparticles DGPX4@401-TK-12 HI, PE, CC ∼200 HT-1080 HT-1080 tumor-bearing mouse xenograft Chemotherapy [ 254 ] Epigenetic repression alleviation Nanocarriers PEI@HSANCs EA, PE 164.2 ± 22.4 293T, U937, HL60 AML tumor-bearing mice Immunotherapy [ 256 ] a Abbreviation in the table: EA: electrostatic adsorption, VDW: van der Waals forces, HI: hydrophobic interaction, PE: physical encapsulation, CC: covalent coupling, RR: redox reaction, CI: coordination interaction, HGI: host-guest interaction, BF: biomimetic functionalization, GEF: genetic engineering functionalization.

Mitochondrion-targeting strategies

Mitochondria are ubiquitous in eukaryotic cells and serve as semi-autonomous organelles consisting of a bilayer of membranes, playing a pivotal role in regulating cell survival and apoptosis [ 36 ]. On one hand, mitochondria function as the “powerhouse” of the cell, producing adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) to generate energy and maintain cellular proliferation, differentiation, and growth [ 37 ]. On the other hand, mitochondria act as suicidal “weapon stores”, contributing to the regulation of various cell death pathways, including apoptosis, ferroptosis, pyroptosis, and immunogenic cell death [ 38 ].

Structurally, mitochondria are dynamic organelles composed of four main components: the outer mitochondrial membrane (OMM), the intermembrane space, the inner mitochondrial membrane (IMM), and the mitochondrial matrix [ 39 , 40 ]. The OMM serves as the boundary membrane and contains numerous receptors that selectively recognize and permit specific substances to enter the mitochondria. It also facilitates molecular permeation and signal transduction through voltage-dependent anion channels (VDACs) [ 41 ]. The IMM features a folded structure forming mitochondrial cristae, which play a critical role in key biochemical processes, e.g., the electron transport chain and OXPHOS pathway, thereby driving ATP synthesis and energy metabolism [ 42 , 43 ].

Furthermore, in tumor cells, mitochondria exhibit a substantially more negative membrane potential (−220 mV) compared to normal cells (−140 mV), which is referred to as the mitochondrial membrane potential (ΔΨ m ) [ 24 , 44 ]. This potential difference significantly increases the mitochondrial uptake of lipophilic cationic complexes (up to 1000 times that of extracellular complexes) [ 45 ]. This distinctive feature serves as a crucial basis for the design of mitochondrion-specific therapeutic and diagnostic nanomaterials [ 46 , 47 ].

Numerous mitochondrion-targeting therapeutic strategies have been shown to kill cancer cells through a variety of perturbation mechanisms, including interfering with the mitochondrial structure, mtDNA, metabolism, redox state, protein modulation as well as calcium homeostasis [ 48 ]. These mitochondrion-targeting therapeutic strategies are illustrated in detail below.

Mitochondrion-targeting agents

As mentioned before, mitochondria can work as both “powerhouses” and “weapon stores”, modulating cellular life and death. Notably, the unique physical and chemical characteristics of mitochondria, such as their sizable negative membrane potential, complex bilayer membrane structure, and high impermeability, have been extensively studied over the past few decades [ 24 , 49 ].

When designing mitochondrion-targeting nanodrugs, it is essential to pay close attention to these structural characteristics. For example, positively charged nanostructures can significantly enhance mitochondrial binding and increase local drug concentration, as demonstrated by delocalized lipophilic cations (DLCs) and transition metal complexes. Furthermore, the nanostructures with efficient membrane-penetrating capabilities, such as mitochondrion-permeable peptides (MPPs), can further improve mitochondrial permeability. By leveraging these design strategies, therapeutic efficacy can be greatly improved while minimizing drug-related side effects ( Fig. 4 ) [ 50 ]. Fig. 4 Structure design of mitochondrion-targeting agents. Fig. 4

Delocalized lipophilic cations

Lipophilic cations have become the most prevalent type of molecules employed in mitochondrion-targeting DDSs [ 51 ]. Due to the negative membrane potential (−220 mV) and high lipid content of mitochondria in tumor cells, lipophilic cations can be rapidly, smoothly, and selectively transported across the mitochondrial membrane system [ 24 ]. In fact, it has been found that lipophilic cations can result in a 100-500-fold accumulation in mitochondria for every 61.5 mV change of ΔΨ m at 37 °C [ 52 ].

It is now widely recognized that DLCs enhance mitochondrial targeting capability, as mitochondria rapidly absorb them without the need for specific transport mechanisms [ 53 ]. Several DLCs have been reported, including the triphenylphosphonium (TPP) ion, dequalinium, cyclometalated iridium( iii ) complexes, berberine, rhodamine19, rhodamine123, and guanidine/biguanide [ [54] , [55] , [56] , [57] , [58] ]. The chemical structures of various DLCs and antitumor drug-DLC conjugates have been summarized in detail [ 59 ].

Among them, TPP cations have been prevalently employed in the construction of mitochondrion-targeting nanosystems, including various biomolecular probes and therapeutic agents [ 60 ]. TPP can interact with the hydrophobic IMM, induce lysosomal escape, become localized in the mitochondria, and accumulate in the mitochondrial matrix after passing through the lipid bilayers. Hu et al. developed smart nanocomposites (AIBI@H-mMnO 2 -TPP@PDA-RGD, AHTPR) based on the excellent mitochondrion-targeting ability of TPP [ 48 ]. These nanocomposites effectively induced tumor cell death by producing oxygen-irrelevant free radicals. Overall, DLCs constitute a very promising option for mitochondrion-targeting tumor therapy.

Transition metal complexes

Metal complexes consist of metal atoms or ions surrounded by coordinating ligands. According to recent studies, metal complexes containing easily-modified coordination ligands and various transition metals, including iridium( iii ), gold( iii ), copper, europium, manganese, platinum, cobalt, nickel, zinc, rhodium, antimony, and osmium, exhibit the ability to target mitochondria [ 61 , 62 ].

In addition, due to their distinctive photophysical (luminescent) properties, photothermal properties, and ability to produce reactive singlet oxygen molecules ( 1 O 2 ), transition metal complexes can be used to create photodynamic and photothermal agents in photodynamic therapy (PDT) and photothermal therapy (PTT) [ 63 ]. For example, Liu et al. fabricated mini-sized S-nitrosothiol-loaded Au@silica nanorods that, under near-infrared (NIR) irradiation, could elicit collagen depletion and mitochondrial damage [ 63 ].

Therefore, these species typically exhibit strong mitochondrial affinity (attributed to their substantial positive charge), potent therapeutic efficacy (via induction of ΔΨ m depolarization), as well as remarkable structural stability [ 61 , 62 ]. As a result, they have become an indispensable component in the arsenal of tumor treatment strategies.

Mitochondrion-permeable peptides

Focusing on the characteristics of the mitochondrial complex bilayer membrane structure and its high impermeability, researchers have discovered that MPPs can enhance the penetration efficiency of DSS [ 64 , 65 ]. MPPs are certain short synthetic peptides that harbor reduplicative lipophilic residues and cationic hydrophobic residues, such as ( l -cyclohexyl alanine- d -arginine)3, which is abbreviated to (F x ,r)3 [ 64 ]. MPPs can thus permeate cells and accumulate in the mitochondria in human tumor cells with minimal toxic side effects [ 65 ].

One notable advantage of MPPs, compared to DLC systems, is their customizable peptide sequence or structural motif, which can be rationally designed depending on its requirements, such as precise mitochondrial targeting. Considering these factors, Lo et al. constructed self-destructive, pH-sensitive polyethylene glycol (PEG) shell-modified liposomes and solid lipid nanoparticles [ 66 ]. These nanoparticles were comprised of mitochondrion-directing apoptosis-inducing peptides and one cell-penetrating peptide (CPP) with high potency and selectivity towards human tongue squamous carcinoma cells (SAS cells) associated with head and neck cancer. This design enhanced the uptake and release of miR-200 and irinotecan into the SAS cells, effectively inducing apoptosis. Additionally, these peptides were specifically engineered to act as nanovectors for irinotecan and miR-200, thereby improving the accumulation of tumor-specific drugs.

Mitochondrial DNA perturbation

In humans, mtDNA is a circular double-stranded DNA (made up of over 16,500 base pairs) that contains 13 polypeptide-encoding genes and transcription information [ 67 ]. mtDNA encodes respiratory chain polypeptides critical for OXPHOS, fueling tumor initiation, growth, and metastasis [ 68 , 69 ]. In the absence of histone protection and inefficient DNA repair capacity, mtDNA is more susceptible to reactive oxygen species (ROS)-induced DNA damage than nuclear DNA (nDNA), thereby more easily triggering the initiation of programmed cell death (PCD) [ 70 ]. Consequently, mtDNA has emerged as a significant target for tumor therapy [ 71 ].

For instance, Zhao et al. engineered a herpesvirus-mimicking nanoparticle (named Vir-ZM@TD) for breast tumor treatment ( Fig. 5 a) [ 72 ]. By emulating the serial infection processes used by herpesviruses, the nanoparticle was able to induce TFAM (transcription factor A, mitochondrial) deficiency-triggered mtDNA stress. This ultimately led to the priming of the cGAS-STING pathway-mediated innate immunity response in tumor cells. Remarkably, the approach resulted in the complete regression of 68 % of the primary tumors in 4T1-tumor-bearing mice. However, it is worth noting that the immune regulatory mechanisms mediated by mtDNA release remain incompletely understood. While mtDNA release can activate the cGAS-STING pathway and elicit antitumor immune responses, not all tumor types exhibit sensitivity to this pathway [ 73 , 74 ]. Moreover, sustained mtDNA release may trigger chronic inflammation, potentially leading to immune tolerance or facilitating tumor immune evasion [ 75 ]. Fig. 5 Schematic illustrations showing different nano-targeting systems achieving precise mitochondrial localization and killing tumor cells through mtDNA perturbation (a–b) and metabolism disruption (c–d). (a) Vir-ZM@TD mimicked herpesvirus infection to trigger innate immunity in tumor therapy. ATP-responsive DNAzymes cleaved TFAM mRNA, causing mtDNA stress [ 72 ]. (Reproduced with permission, copyright 2022, Wiley-VCH.) (b) MIDRS comprised DNA/Mg 2+ nanoflowers with cytochrome C aptamer, Cas12a/crRNA, and quenched chlorin e6 (Ce6). MIDRS remained inert in circulation but disrupted mitochondrial respiration in tumor cells. Cas12a recognized mtDNA SNVs, releasing Ce6 to restore photosensitivity. Laser irradiation generated ROS, damaging mitochondria and activating the cGAS-STING pathway to enhance immune response [ 76 ]. (Reproduced with permission, copyright 2023, Science.) (c) PEG and TPP functionalized the 2D WS 2 nanosheets to load glycolysis inhibitor FX11. FX11@TPEG-WS 2 targeted mitochondria via TPP and induced apoptosis by disrupting glycolysis under ultrasound [ 90 ]. (Reproduced with permission, copyright 2023, Wiley-VCH.) (d) TDNs-G-TPP targeted mitochondrial energy metabolism, inhibiting aerobic respiration and glycolysis, reducing ATP production, and blocking lamellipodia formation to suppress migration of tumor cells [ 98 ]. (Reproduced with permission, copyright 2022, American Chemical Society.) Fig. 5

Likewise, Li et al. fabricated a mutation-induced drug release system, called MIDRS, consisting of programmable DNA/Mg 2+ hybrid nanoflowers ( Fig. 5 b) [ 76 ]. This nanosystem employed the single nucleotide variation (SNV) recognition ability and trans-cleavage activity of Cas12a to convert tumor-specific mtDNA mutations into a regulatory switch for intracellular drug release, thus realizing the precise killing of tumor cells. However, the high heterogeneity of mtDNA mutations within tumors presents a challenge for mtDNA-targeting strategies, which may require personalized genetic screening approaches, such as Cas12a-mediated recognition of specific mutations [ 77 ]. This reliance could significantly increase the complexity and cost of clinical implementation, potentially hindering large-scale application.

In summary, tumor cells have a more extensive metabolic reprogramming capacity in order to meet their need for immortality. This makes them more sensitive and susceptible to mitochondrial disruption compared to normal cells [ 78 ]. Moreover, mtDNA mutation in tumor cells is relatively frequent which may lead to mitochondrial dysfunction and thus promote tumorigenesis [ 79 ]. Thus, interfering with mtDNA gene delivery may have great potential in precise tumor therapy. However, overcoming the individualized limitations posed by the high heterogeneity of mtDNA and striking a balance between immune activation and the potential risk of immune evasion in clinical settings remain critical challenges for future research [ 80 ].

Metabolism disruption

Substance metabolism inhibition

Tumor cells rely on aerobic glycolysis, rather than OXPHOS, to meet their rapid energy demands, even with sufficient oxygen - a phenomenon known as Warburg effect [ 81 ]. This process generates less ATP while increasing glucose consumption and lactate production [ 82 , 83 ]. It is believed that this phenomenon may be linked to mitochondrial dysfunction [ 84 , 85 ].

Aerobic glycolysis generates metabolites such as nucleotides, lipids, and amino acids, which fuel tumor cell growth and proliferation [ 86 , 87 ]. Consequently, inhibiting glycolysis interferes with cellular activity and effectively “starve” tumor cells, offering a potential therapeutic strategy [ 88 , 89 ]. However, conventional aerobic glycolysis inhibitors often cause adverse effects due to their untargeted feature and inefficient delivery method. In contrast, emerging studies highlight the potential of mitochondrion-targeting nanodrugs to address these limitations effectively.

Taking these factors into consideration, Haong et al. developed tungsten disulfide (WS 2 ) nanosheets loaded with FX11 (a glycolysis inhibitor) and TPEG (FX11@TPEG-WS 2 ) ( Fig. 5 c) [ 90 ]. These nanosheets selectively targeted mitochondria in tumor cells, where FX11 inhibited glycolysis and disrupted energy metabolism. Upon ultrasound irradiation, they exhibited remarkable antitumor efficacy by combining a piezodynamic therapeutic effect, driven by ultrasound-induced ROS generation, with mitochondrial energy metabolism inhibition via the 2D WS 2 nanosheets.

Energy metabolism interference

Mitochondria generate ATP via OXPHOS and the electron transport chain, fulfilling cellular energy requirements [ 42 ]. Due to their heightened energy demands driven by active glycolysis, tumor cells exhibit elevated ATP levels, presenting a critical therapeutic target [ 91 , 92 ]. Notably, tumor cells exhibit ATP-dependent MDR characteristics. For example, P-glycoprotein and other ATP-binding cassette transporters can promote drug efflux in an ATP-dependent manner, thereby reducing lowering intracellular drug concentrations and reducing their toxicity in tumor cells, and ultimately leading to MDR [ 93 ]. Thus, ATP-inhibition strategy might help overcome MDR [ 94 ]. For example, Deng et al. designed a mitochondrion-targeting nitric oxide (NO) delivery nanoplatform (α-CD-DOX-NO-DA) that could precisely deliver NO in response to doxorubicin (DOX) release and depletion of mitochondrial ATP levels [ 95 ]. It thus inhibited the P-glycoprotein activity to overcome MDR and enhanced the efficacy of the chemotherapy.

In addition, tumor-derived microvesicles (TMVs) play an essential role in tumor growth and metastasis [ 96 ]. However, the production and release of TMVs is energy-consuming and dependent on the mitochondrial ATP. Therefore, ATP depletion also inhibits TMV formation and produces antimetastatic effects in tumors [ 97 ]. For example, Li et al. developed an intracellular K + -mediating dynamic assembly of DNA tetrahedrons ( Fig. 5 d) [ 98 ]. The DNA aggregates targeted mitochondria, acting as a polyanionic barrier that suppressed ATP production, depriving cells of energy and functioning as starvation therapy. Overall, energy metabolism disruption could be a promising option for tumor treatments in the future.

Redox state imbalance

Mitochondrial reduction-oxidation (redox) homeostasis is a defense mechanism which maintains a balance between ROS and antioxidants such as glutathione (GSH). Most tumor cells (due to oncogenic stimuli and their highly active metabolism) are characterized by elevated ROS, generally referred to as “oxidative stress” [ 99 ]. This oxidative stress makes tumor cells more vulnerable to exogenous substances and disrupts redox balance [ 100 ]. Excess ROS in mitochondria usually cause irreversible damage to the lipids, proteins, and mtDNA, leading to a “butterfly effect” of mitochondrial dysfunction [ 101 , 102 ]. Therefore, increasing ROS levels beyond a critical threshold can lead to mitochondrial dysfunction, such as OMM permeabilization and mtDNA damage, which may ultimately trigger PCD [ 103 , 104 ].

Numerous studies have shown that multiple nanodrugs can favorably modulate the release and clearance of ROS. Dai et al. recently fabricated a mitochondrion-targeting supramolecular nanocarrier, referred to as T-NP CA/NO , for the co-delivery of cinnamaldehyde and NO [ 105 ]. After the nanocarrier was internalized by tumor cells, the NO was accurately targeted to mitochondria, facilitating mitochondrial membrane permeabilization and depletion of GSH. This amplified the ROS-generating effect of cinnamaldehyde in mitochondria, thus realizing reactive nitrogen species (RNS)-mediated oxidative therapy. However, it is crucial to recognize that a single model for mitochondrial ROS regulation may not be well-suited to the diverse ROS metabolic profiles of different tumor subtypes. This heterogeneity can significantly affect treatment efficacy [ 106 ]. Future research could leverage single-cell metabolomics to develop personalized, smart-responsive nanoparticle DDS, thereby enabling more precise and effective tumor therapies [ 107 ].

Mitochondrion-associated protein modulation

As previously mentioned, human mtDNA encodes 13 essential protein structures that regulate oxidative stress, energy metabolism, ion homeostasis, and other cellular processes [ 108 ]. Consequently, inhibiting the synthesis of these mitochondrial proteins or inducing their dysfunction within tumor cells could serve as a targeted strategy to trigger cell death [ 109 ].

Zhou et al. designed a photothermally-triggered nanoplatform (Au@MSN-Cu/PEG/DSF) with an extraordinarily high tumor inhibition rate of 80.1 % [ 110 ]. The nanoplatform generated copper ion in situ , which aggregated harmful mitochondrial lipoylated proteins and destabilized iron-sulfur cluster proteins in the tricarboxylic acid cycle. This, ultimately, resulted in cell cuproptosis. Similarly, He et al. constructed nanoparticles of a peptide-lipid conjugate, Flag-(C16) 2 , to serve as a substrate for enterokinase and encapsulate chloramphenicol, a clinically-used antibiotic [ 111 ]. Peri-mitochondrial enterokinase cleaved the Flag-tag on the conjugate to exclusively deliver chloramphenicol into the mitochondria of tumor cells, thus inhibiting the synthesis of mitochondrial proteins, inducing the release of cytochrome C into the cytosol, and ultimately leading to the demise of the tumor cells. In brief, designing nanodrugs that can disrupt mitochondrial proteins offers an effective approach to target and kill tumor cells.

Mitochondrial calcium homeostasis regulation

Mitochondrial calcium ions (Ca 2+ ) are distributed in the intermembrane space, and their homeostasis helps support ATP production, signal transduction, and redox balance [ 112 , 113 ]. Previous studies have shown that tumor cells are more sensitive to fluctuations in Ca 2+ than healthy cells [ 114 ]. Excessive Ca 2+ in mitochondria can severely damage the mitochondria, trigger the release of cytochrome C, and activate caspase-3, ultimately inducing apoptosis in tumor cells [ 24 , 114 ].

Consequently, responsive Ca 2+ nanodrugs based on calcium carbonate, calcium peroxide, and calcium phosphate have been developed to disrupt mitochondrial Ca 2+ homeostasis for tumor therapy [ 24 ]. For example, Wu et al. fabricated an antitumor nanodrug combining calcium overload and photoimmunotherapy utilizing mitochondrial N770-conjugated mesoporous silica nanoparticles loaded with CaO 2 (CaO 2 -N770@MSNs) for colorectal cancer treatment [ 115 ].

Furthermore, Ca 2+ -regulated gene therapy strategies present new avenues for mitochondrion-targeting tumor therapy. For instance, Yan and collaborators developed a self-catalytic multicomponent deoxyribozymes (MNAzymes) system for tumor-specific PTT [ 116 ]. They prepared DSPE-PEG-RGD micelles loaded with IR780 and calcium efflux pump inhibitor curcumin, with MNAzymes embedded in the PEG layer and sealed with calcium phosphate. Ca 2+ in this system could promote the enzymatic degradation of miRNA-21, cleaving the mRNA of heat shock protein-70 (HSP70), thereby effectively inhibiting the production of HSPs and enhancing the effectiveness of PTT in pancreatic cancer.

Nucleus-targeting strategies

The nucleus, unique to eukaryotic cells, houses the genome, facilitates DNA storage and synthesis, and transcribes various RNA, including mRNA, tRNA, rRNA, and noncoding RNAs [ 117 ]. It also regulates metabolism, growth, proliferation, gene activation, and cell cycle, acting as the cell's “commander”.

Structurally, the nuclear envelope (NE) encloses the contents of the nucleus, consisting of an inner and outer nuclear membrane, separated by a 20–24 nm perinuclear space connected to the ER [ 118 ]. As a compartment border, the NE protects the genetic materials in the nucleus, while allowing versatile communication between the nucleus and cytoplasm via nuclear pore complexes (NPCs) [ 17 , 119 ]. Each NPC, composed of nucleoporins (Nups), facilitates selective nucleocytoplasmic exchange essential for cell proliferation, metabolism, and growth. Transmembrane Nups anchor NPCs to the NE, while fiber-like extensions within the pore form a selective hydrogel regulating substance passage [ 120 ].

As previously mentioned, the nucleus stores genetic information, consisting of both DNA and proteins in the chromatin or chromosomes with its organized structure driven by chromosome arrangement, impacting gene expression [ 121 ]. The nucleolus, a nuclear subregion, synthesizes ribosomes and regulates mitosis, cell cycle, and stress responses [ 122 ].

The structural and functional abnormalities of the nucleus are closely associated with the development and progression of cancer. Modifying nanodrugs to leverage the unique structural and functional characteristics of the nucleus, such as nuclear morphology, nuclear pore integrity, and nDNA expression, can help alter and optimize their physicochemical properties, enabling efficient drug delivery to nucleus. This approach represents a critical strategy for precise cancer therapy.

Nucleus-targeting agents

The substance exchange between nucleus and cytoplasm is a highly selective process, posing significant challenges for drug delivery to the nucleus. To address this, researchers focus on enhancing nuclear recognition and binding capabilities (e.g., by modifying nanodrugs with nuclear localization signal peptides or transactivator of transcription peptides) or expand nuclear pores (e.g., using dexamethasone) to further improve the nuclear penetration efficiency of nanodrugs ( Fig. 7 a–c).

Nuclear localization signal modification

The NPCs, embedded in the NE, serve as the primary transport channels for molecular exchange between the nucleus and the cytoplasm [ 120 ]. While most small molecules can pass freely through these “gates”, certain macromolecules, such as proteins, cannot. Instead, they must be “tagged” with an amino acid sequence, commonly referred to as a nuclear localization signal (NLS) peptide, which acts as a “key” to unlock these gates, enabling the translocation of the macromolecule through the nuclear pores.

In the context of nucleus-targeting tumor therapy, this mechanism has been exploited to improve the precision of drug delivery. For example, Du et al. engineered a variety of biodegradable silica nanocapsules (BSNPs) whose surfaces were modified with different NLS peptides ( Fig. 6 ) [ 123 ]. The modified nanocapsules facilitated the effective delivery of nucleus-targeting proteins, including enhanced green fluorescent protein, anti-histone H3 monoclonal antibody (mAb H3 ), and deoxyribonuclease I (dNase I). With the assistance of the NLS modification, efficient apoptosis of tumor cells was achieved by delivering the dNase I to the nuclear interior. Likewise, a nanodevice that could selectively pass through the nucleus of tumor cells was created by Cui et al. Their nanodevice utilized NLS-tagged porphyrin species, which targeted the nucleus and generated 1 O 2 upon laser irradiation [ 124 , 125 ]. Fig. 6 Schematics of using NLS peptide modifications for nucleus-targeting nanodrug design. (a) Illustration of various sequences of NLS peptides used to modify endosomolytic peptide L17E. (b–c) The protein@BSNP-NLS/L17E complex cloaked with CM was delivered via intravenous injection. (d) Intravascular delivery and homologous targeting of membrane-cloaked protein@BSNP-NLS/L17E-M. (e) Intracellular protein-delivery pathways: endolysosomal entrapment without L17E (f) and nuclear delivery with L17E (g) [ 123 ]. (Reproduced with permission, copyright 2023, Elsevier Ltd.) Fig. 6 Fig. 7 Structure design of nucleus and lysosome-targeting agents. (a–c) Nucleus-targeting agents. (d–e) Lysosome-targeting agents. Fig. 7

Transactivator of transcription peptides

Transactivator of transcription (TAT) peptides are CPPs that are widely used in the modification of DDSs. The amino acid sequence GRKKRRQRRRPPQ in TAT peptides can be recognized by NPCs. By conjugating substances like nanodrugs (which cannot directly enter the nucleus via passive diffusion) with TAT peptides, the complexes can accurately target and penetrate nucleus through NPCs to exert their therapeutic effects [ 126 , 127 ]. For example, to endow nanoparticles with qualified nucleus-targeting ability, Wang et al. decorated PEG-modified Ir NCs with αvβ3 integrin-targeting cyclic arginine-glycine-aspartic (c(RGDyC)) and TAT peptides (designated as Ir-RGD-TAT NCs or Ir-R/T NCs for short). The TAT-modified Ir-R/T NCs were thus transported into the nucleus at the NPCs (via importin α and β), allowing the Ir-R/T NCs to accumulate in the nucleus and facilitating precise nucleus-targeting tumor therapy [ 128 ]. Similarly, Li et al. designed a TAT-peptide-modified mesoporous silica nanoparticle (MSN). An alternating magnetic field released TAT peptides and let nanoparticles penetrate the nucleus. The combination of thermotherapy and hypoxia-activated chemotherapy thus led to an exhaustive apoptosis of cancer stem cells [ 129 ].

Dexamethasone

Besides modifying signaling proteins for synergistic targeting, expanding nuclear pores to aid nanodrug entry is another effective way to improve targeting efficiency. Several studies have discovered that dexamethasone plays a significant role in dilating NPCs. Researchers found that NPCs in African Xenopus oocytes were induced to dilate within minutes after injection of the glucocorticoid analog, dexamethasone [ 130 , 131 ]. Based on this concept, Karandish et al. synthesized an alkyne-dexamethasone derivative and conjugated it to N 3 -PEG-polylactic acid copolymer. The dexamethasone group dilated the NPCs enabling transports of encapsulated drugs into nucleus of pancreatic tumor cells successfully [ 132 ]. Moreover, Xiong et al. proposed MSNs modified with folic acid (FA) and dexamethasone. Dexamethasone induced nuclear pore dilation up to 60 nm during the translocation process, leading to active nucleus accumulation of nanocarriers in HeLa cells and enhancing the inhibition efficacy of DOX [ 133 ].

Structurally tunable nanodrugs

The development of nucleus-targeting nanodrugs is hindered by the nanoscale microstructure of nuclear pores, which presents a substantial barrier to the efficient nuclear entry of nanodrugs [ 134 ]. Notably, the relationship between nanoparticle size and their ability to penetrate the nucleus remains poorly understood [ 135 ]. To overcome this challenge, researchers have increasingly focused on designing nanodrugs with tunable morphology and size to optimize nucleus-targeting drug delivery.

A representative example is the 10-hydroxycamptothecin (HCPT)-peptide conjugate HpYss, developed by Zhan et al. [ 136 ]. This innovative nanostructure mimicked the artificial transformation of extracellular vesicles into filaments, precisely abolishing liver tumor growth and metastasis [ 136 ]. Under sequential stimulation by extracellular alkaline phosphatase and intracellular GSH, HpYss underwent a tandem self-assembly process, transitioning from extracellular nanoparticles (50–100 nm) to intracellular nanofibers (4–9 nm). This size and morphology transformation facilitated highly efficient nuclear drug delivery, markedly enhancing nucleus-targeting capability of HpYss and resulting in over a tenfold improvement in inhibitory efficacy of HCPT against HepG2 cells. Collectively, the development of nanodrugs with tunable morphology and size represents a crucial strategy for achieving efficient nucleus-targeting drug delivery and improving therapeutic outcomes.

Nuclear envelope integrity impairment

Compromising the integrity of the nuclear membrane itself represents a more direct and aggressive approach to delivering drugs to the inner regions of the nucleus. This strategy has been demonstrated in recent research [ 137 ]. Cheng et al. employed a dual-stage PDT strategy, constructing multifunctional chimeric peptide-engineered exosomes to selectively and sequentially disrupt the plasma membrane and NE of tumor cells, inducing cell death and thereby achieving tumor growth inhibition [ 137 ]. Besides, artificially-created nanodrugs can also be utilized to disrupt the nuclear membrane and hence allow macromolecules to enter the nucleus and disrupt its function. Examples here include the use of short-lived vapor nanobubbles generated by perinuclear gold nanoparticles (AuNPs) and PEG-POSS-RB nanoparticles [ 138 , 139 ]. In the former example, Houthaeve et al. developed a photoporation method in which nanobubbles were generated by wide-field laser illumination of perinuclear-localized AuNPs [ 138 ]. The nanobubbles subsequently caused mechanical damage to the NE and promoted the inflow of certain medical macromolecules into the nucleus.

Nuclear DNA perturbation

Numerous nanodrugs have been shown to effectively kill tunmor cells by inducing DNA damage or interfering with DNA-related biological processes. The primary mechanisms underlying current nucleus-targeting therapies include DNA strand breakage, ROS-induced DNA lesions, interference with DNA synthesis and expression, as well as disruption of nuclear telomere structures [ 140 , 141 ].

DNA strand breakage

In radiation therapy, ionized atoms and free radicals are generated by the decay of the radioisotope used, which can subsequently break single strands of DNA. Radiosensitizers are commonly used to significantly enhance the therapeutic efficiency of radiotherapy by markedly increasing the damage to nDNA [ 140 ]. In the study conducted by Wang et al., the Ir-R/T species they developed accurately targeted and accumulated inside the nucleus of tumor cells [ 128 ]. Upon subsequent X-ray irradiation, the Ir-R/T species were very effective at generating DNA lesions, resulting in enhanced nucleus-targeting antitumor therapy.

Reactive oxygen species induced DNA lesion

Certain antitumor drugs, like DOX, can induce DNA damage by generating ROS within the nucleus. For example, Zhang et al. employed a carbon-based nanomaterial (CBN) as a nanocarrier to design a new nanodrug delivery system CBN-Pluronic F127-DOX (CPD) [ 142 ]. The system efficiently caused the accumulation of DOX in the nucleus of tumor cells, leading to substantial ROS production and inhibition of tumor growth in vivo . Likewise, Zhao et al. developed an innovative nanodrug through the successive encapsulation of MnO 2 nanoparticles and iron carbonyl [ 143 ]. This nanodrug could thus generate both ROS and CO, enabling the simultaneous targeting of both the nucleus and mitochondria and extensively damaging them in tumor cells.

DNA synthesis disruption

DNA synthesis can be disrupted by interfering with their signaling pathways. This can disorder the cell cycle and hence hinder the synthesis process. For instance, SOX17 has been identified as an upstream repressor of the transcription factor NRF2 [ 144 ]. Lowering the expression of SOX17 leads to a higher expression of NRF2, which leads to a diminished response to concomitant chemo-radiation therapy in tumor cells and reduces the patients’ survival rate. Carboxymethyl cellulose-coated zero-valent-iron (ZVI@CMC) was designed to restore SOX17 protein expression which decreased the expression of NRF2 and thus inhibited tumor growth. Likewise, Ru@SiO 2 -PA and nickel nanoparticles (Nano-Ni) were fabricated to produce similar DNA-damaging effects in tumor cells thereby killing them [ 145 , 146 ].

DNA expression interference

Tumorigenesis and progression are primarily driven by dysregulated cell growth, characterized by oncogene activation and tumor suppressor gene inactivation [ 147 ]. In tumor research, exogenous genes, including dsDNA, ssDNA, plasmid DNA, and siRNA, have been developed to disrupt, eliminate, or correct tumor-associated genetic defects and abnormalities [ 17 ]. These approaches enable the modulation of endogenous gene expression and hold promise for permanent tumor eradication [ 147 ]. When combined with nanomedicines, gene therapy strategies provide a robust approach to regulating tumor-related gene expression by interfering with nDNA expression. This integration facilitates precise targeting of the nucleus, thereby enhancing tumor-killing efficacy [ 17 ]. Metal-nucleic acid frameworks (MNFs), a type of emerging functionalized nanostructures, combine metal ion catalysis with gene therapy effects to create multifunctional therapeutic platforms [ 148 ]. For instance, Yan et al. designed an interferon regulatory factor-1(IRF-1) loaded Ca 2+ /(aptamer-deoxyribozyme) MNF nanoplatform (IRF/H-GDz/Ca) that efficiently silenced the expression of GLUT1 gene within the nuclei of tumor cells [ 148 ]. This disruption impaired the pentose phosphate pathway and NADPH synthesis, leading to disturbances in ATP depletion, and DNA damage in tumor cells. Additionally, IRF-1 in the nanoplatform significantly suppressed RAD51 expression, impairing RAD51-mediated homologous recombination DNA repair, with gastric tumor inhibition rate up to 90 %.

Nuclear telomere structure disruption

Telomeres, as distinctive features of chromosomal structure, represent an important target for disruption. It is noteworthy that telomeric repeat-binding factor 2 (TRF2) is a pivotal telomere-binding protein responsible for maintaining telomere structure and function. Recently, a lipid nanoparticle-modified siRNA, miR-182–3p, was designed to inhibit TRF2 expression, leading to DNA damage at telomeric and periplasmic sites. This, in turn, triggered extensive apoptosis in tumor cells of triple-negative breast cancer [ 149 ].

However, it is worth noting that tumor cells have a robust DNA repair capacity, enabling them to efficiently repair DNA damage induced by nanodrugs. For instance, DNA breaks induced by radiation therapy or ROS can be repaired by tumor cells via non-homologous end joining or homologous recombination, thus diminishing treatment efficacy [ 150 ]. Additionally, overexpression of certain genes, such as RAD51, can boost DNA repair mechanisms, leading to resistance to treatment [ 151 , 152 ]. Therefore, a single nDNA-damaging strategy may not yield sustained antitumor effects, and combining approaches that inhibit DNA repair could enhance therapeutic outcomes.

Lysosome-targeting strategies

Lysosomes, known as the “suicidal bags” of eukaryotic cells, are another organelle that can be targeted in tumor cells [ 153 ]. These dynamic organelles are essential for the degradation, clearance, and recycling of cellular waste [ 154 , 155 ].

Lysosomes are spherical or ellipsoidal vesicles, approximately 1 μm in diameter, containing a unique acidic lumen that provides an optimal environment for acid hydrolases (pH 4.5–5) [ 156 , 157 ]. The acidic environment is maintained by the action of proton pumps (V-ATPases), ion channels, and membrane transport proteins embedded in the lysosomal membrane. Together, these components create the ideal conditions for the digestion and breakdown of substrates by hydrolytic enzymes [ 156 , 158 ]. Over 60 hydrolytic enzymes have been found in lysosomes, including sulfatases, proteases, phospholipases, and phosphatases. These enzymes play pivotal roles in degrading and recycling macromolecules (polysaccharides, proteins, and nucleic acids), organelles, exogenous substances (through endocytosis and phagocytosis), and intracellular debris (via a kind of autophagy called macroautophagy), thus maintaining cellular homeostasis [ 159 , 160 ].

Notably, the lysosomes in tumor cells have larger and relatively more fragile membranes, compared to those in normal cells. They also exhibit greater cathepsin activity. These differences make tumor cells more susceptible to endogenous or exogenous stimuli that affect lysosomal membrane permeabilization (LMP), which can ultimately lead to lysosome-dependent cell death [ 161 ]. From this perspective, lysosome-targeting strategies can be designed around several key approaches: targeting specific lysosomal structures, inducing LMP, and mediating lysosome-dependent cell death.

Lysosome-targeting agents

Lysosomal sorting peptides

In intracellular transport, protein sorting to lysosomes is guided by lysosomal sorting peptides (LSPs), mainly classified as tyrosine-based or dileucine-based signals [ 162 ]. Researchers have demonstrated that fusing a lysosomal sorting motif to CPPs can help ensure the targeted delivery of nanoparticles to lysosomes ( Fig. 7 d) [ 163 ]. For example, Dekiwadia et al. decorated 13-nm AuNPs with CPPs and LSPs with sequences YQRLC and CNPGY, both of which enhanced lysosomal uptake [ 164 ]. Similarly, Zhang et al. conjugated LSPs, phosphonate, and amine onto the surface of MSNs (YQRLGC). Due to the proton sponge effect, YQRLGC increased the accumulation of MSNs in lysosomes (up to 32 %), which held promise for offering new tools for lysosome-targeting tumor therapy [ 165 ].

Morpholine

Morpholine is a secondary amine with intrinsic basicity, capable of adapting to the acidic environment of lysosomes and exerting its effects. This unique property makes morpholine a highly promising agent for lysosome-targeting applications ( Fig. 7 e) [ 166 , 167 ]. Based on this, Wang et al. developed a dual-targeted liposomes by integrating curcumin with both a morpholine moiety and a galactose moiety [ 168 ]. While curcumin induced tumor cell apoptosis via the LMP pathway, its therapeutic effect on hepatocellular carcinoma was limited by poor selectivity. To address this limitation, the galactose moiety was incorporated to specifically recognize ASGPR, which was overexpressed on hepatoma cells, thereby improving selectivity. Meanwhile, the morpholine group further enhanced the lysosomal targeting efficiency of the liposomes.

Lysosome membrane permeabilization induction

LMP has been demonstrated to cause extensive lysosomal leakage, leading to cytoplasmic acidification and subsequent uncontrolled degradation of cellular components, ultimately triggering lysosome-dependent cell death [ 169 ]. Furthermore, lysosomes in tumor cells are more vulnerable to LMP due to their enlarged size and number, special biogenesis, altered HSP70, as well as lysosomal-associated membrane protein 1 expression [ 170 ].

Exquisitely-designed nanostructures can effectively eliminate tumors by inducing LMP. Their primary mechanisms involve the generation of thermal or oxidative stress, or increasing lipid peroxidation. These processes cause LMP and release of proteolytic enzymes into the cytosol, thus prompting cell death via lysosome-associated pathways [ 168 , 171 ]. For example, Lin et al. synthesized Fenton-type copper peroxide nanodots (CPNDs) in chemodynamic therapy (CDT) [ 172 ]. CPNDs decomposed in the acidic lysosome environment, thus supplying H 2 O 2 and copper ion which acted as a Fenton catalyst to produce hydroxyl radicals. These radicals led to lipid peroxidation, induced LMP and ultimately resulted in the death of tumor cells. Additionally, several nanodrugs with special structural characteristics have also been found to destroy lysosomes through LMP induction. These include lysosomal glycosidases (such as β-hexosaminidase and β-galactosidase), receptor-interacting protein kinase 3, and a pyrene-peptide conjugate, amongst others [ [173] , [174] , [175] , [176] ].

Finally, research has shown that certain nanoparticles with precisely controlled surface charges can provoke LMP as well [ 177 ]. Borkowska et al. fabricated mixed-charge nanoparticles, coated with specific ratios of positively and negatively charged ligands, which selectively targeted lysosomes in tumor cells while exhibiting minimal cytotoxicity toward normal cells [ 177 ]. Inside the lysosomes of tumor cells, these nanoparticles formed unique assemblies and crystals that could not be cleared by exocytosis. As a result, they impaired lysosomal function, ultimately triggering LMP and leading to cell death. However, tumor cells possess a certain level of adaptability and can resist LMP-induced cell death by enhancing lysosomal membrane stability, increasing autophagy activity, and inhibiting cathepsin activity, all of which can reduce treatment efficacy [ 178 , 179 ]. Therefore, by targeting and counteracting these tumor adaptive protective factors, the therapeutic effects of LMP-induced tumor treatments can be further enhanced.

Lysosome-dependent cell death

Lysosome-dependent ferroptosis

Studies have shown that tumor cells have a higher demand for iron compared to normal cells [ 180 ]. Cancer cells store redox-active iron in their lysosomes due to increased metabolism and metalloprotein turnover [ 181 ]. If excess iron ions from this unstable iron pool are released into the cytoplasm, they can promote iron-catalyzed Fenton reactions, and generate ROS. Lipid peroxidation by ROS causes a fatal cellular damage cascade [ 182 ]. Subsequently, ROS-induced LMP releases more lysosomal cathepsins, which damage DNA and cause ferroptosis, a STING1-dependent iron-catalyzed necrosis [ 181 ]. Various nanostructures that modulate iron metabolism, such as copper nanodots (CNDs), iron-based nanoparticles, and TEP-FFG-CRAY nanofibers, have been found to induce ferroptosis ( Fig. 8 ) [ 183 , 184 ]. For example, Feng et al. fabricated CNDs with a single active center for sonodynamic and catalytic effects. Ferroptosis was achieved by blocking lysosome fusion and degradation and interfering with glutathione peroxidase 4 (GPX4) and cystine-glutamate antiporter SLC7A11. Fig. 8 Illustrations of lysosome-targeting nanodrugs for precise tumor treatment via autophagy flux blockage and ferroptosis induction. (a) Schematic illustration of US-activated variable-valence reaction process [ 191 ]. (Reproduced with permission, copyright 2022, Wiley-VCH.) (b) Diagram of TEP-FFG-CRApY self-assembly, morphological transformation, and induction of prostate cancer ferroptosis [ 184 ]. (Reproduced with permission, copyright 2024, Wiley-VCH.). Fig. 8

Lysosome-dependent pyroptosis

Pyroptosis is a lytic form of PCD triggered by inflammasomes. Its pro-inflammatory response may help induce high antitumor immunity [ 185 ]. After an inflammatory response is stimulated, cysteine proteases (e.g. caspase-1/11/4/5), a hallmark of pyroptosis, are activated to decompose gasdermins (the key protein family in pyroptosis) [ 186 , 187 ]. The degradation products of gasdermins can bind to the CM, forming pores that induce cell swelling and the formation of large bubbles, ultimately leading to cell death. Ploetz et al. developed a lipid-coated metal-organic framework based on iron nanoparticles to deliver large amounts of iron ions into cells [ 188 ]. The degradation of the metal-organic framework was found to trigger lysosomal rupture and pyroptosis. Pyroptosis was mediated by caspase activation, which triggered gasdermin activation and interleukin-1β-release followed by gasdermin D cleavage, cell swelling, and lysis [ 189 , 190 ].

Endoplasmic reticulum-targeting strategies

The ER is an extensive cytoplasmic membrane network stretching from the nuclear envelope (NE) to the cell periphery. Acting as a hub for lipid and protein biosynthesis, its structure resembles a maze of tubules and saccules in the cytoplasm [ 192 ]. Fundamentally, the ER is comprised of a single continuous membrane that forms an intricate network of diverse domains, each with distinct structures and functions. These domains encompass the peripheral ER and NE, both of which are composed of two flat ER membrane bilayers [ 193 ].

ER is involved in various functions including protein transport, calcium storage, and immunity regulation required for intracellular homeostasis [ 192 , 194 ]. Numerous factors can interfere with the proper folding and post-translational modification of secretory and transmembrane proteins within the ER. As misfolded proteins pile up, ER stress ensues [ 195 ]. Cells then initiate the unfolded protein response (UPR) to recycle or remove harmful proteins [ 196 ].

Ca 2+ stored in the ER is crucial for intracellular signaling regulating cell activities. Indeed, in recent decades, because the Ca 2+ signaling pathway is closely related to cell proliferation and growth, loss of Ca 2+ homeostasis has come to be considered an important driving force involved in the initiation and progression of malignant tumors. Therefore, maintaining the Ca 2+ homeostasis in ER is crucial for proper Ca 2+ signaling and cellular balance [ 197 , 198 ]. Moreover, the ER is closely associated with immune responses. For example, ER-stress-generated ROS can trigger ICD [ 199 ]. Furthermore, the ER protein STING1 plays a pivotal role in the production of type I interferons (IFN-I) and pro-inflammatory cytokines, which regulate autophagic degradation and cell death pathways [ 200 ].

Endoplasmic reticulum-targeting agents

Endoplasmic reticulum retrieval signal

Similar to the NLS that directs proteins to the nucleus, proteins destined for the ER require specific retrieval signals, such as KDEL or KKXX motifs, to be recognized and transported to the ER [ 201 ]. These signals function as molecular “keys”, ensuring proper routing of proteins to the ER for folding, modification, or further transport [ 202 ]. For instance, Wang et al. conjugated AuNPs with a peptide containing the KDEL motif, revealing that these modified AuNPs localized to the ER within 5–15 min, with most accumulating after 1 h [ 202 ]. Furthermore, it was shown that AuNP-KDEL bypassed lysosomal degradation via a clathrin-mediated pathway and trafficked to ER through a retrograde transport mechanism. This novel strategy enabled ER-targeting nanoparticles to evade intracellular degradation and enhance drug efficacy ( Fig. 11 a).

Pardaxin peptides

Pardaxin (FAL) peptides, a CPP derived from fish, have demonstrated the ability to target the ER through a non-lysosomal intracellular transport pathway in a virus-like manner [ 203 , 204 ]. For example, Yin et al. developed a FAL peptide-modified cationic liposome that significantly accumulated in the ER, enhancing gene editing efficiency through the ER-nucleus transport route, highlighting its potential for ER-targeting nanodrug modification [ 205 ]. Additionally, Li et al. assessed the ER-targeting capability of FAL peptides, confirming a specific affinity between FAL peptides and ER. Building on this, they designed an advanced nanosystem incorporating FAL-modified peptides, indocyanine green (ICG)-conjugated hollow gold nanospheres (FAL-ICG-HAuNS), and hemoglobin (Hb) liposomes (FAL-Hb Lipo) to enable PDT and PTT-induced ICD for tumor immunotherapy ( Fig. 11 a) [ 199 ].

Endoplasmic reticulum stress

ER stress refers to a series of self-protective mechanisms activated by cells in response to disruptions in the physiological functions of the ER, caused by endogenous or exogenous stimuli such as hypoxia or nutrient deprivation. It is commonly triggered by abnormal protein folding or Ca 2+ homeostasis imbalances [ 206 ].

Abnormal protein folding

Under physiological conditions, molecular chaperones in ER play a critical role in ensuring proper protein folding. However, under pathological conditions, the accumulation of persistent misfolded proteins leads to ER stress, which triggers an adaptive response known as the UPR [ 207 ]. However, the prolonged or acute activation of the UPR can trigger apoptosis [ 208 ]. As a result, more and more ER-targeting tumor therapies have been developed according to UPR.

Building on this concept, the drug toyocamycin (Toy) is used to target ER and induce ER stress through the UPR [ 209 , 210 ]. For example, Guo et al. designed an advanced redox-responsive nanodrug based on phosphorus dendrimer-Cu 2+ complexes (1G 3 -Cu)-and-Toy-loaded polymeric nanoparticles coated with cancer CMs. The Toy component amplified the ER stress through UPR. Together, these effects induced cell apoptosis and effectively inhibited tumor growth [ 210 ]. In addition, a novel theranostic nanoplatform, consisting of a metal-phenolic-network-coated dendrimer-drug, was designed by Wang et al. to leverage amplified UPR-mediated ER stress with the aid of Toy as well ( Fig. 9 a) [ 209 ]. Fig. 9 Schematic representation of three ER-targeting nanodrugs that induce ER stress. (a) Schematic outline of the ER-targeting tumor therapy process using G5.NHAc-Toy@TF complexes [ 209 ]. (Reproduced with permission, copyright 2021, Wiley-VCH.) (b–c) Steps in UCRSPH nanoparticle synthesis. Enhancing PDT efficacy by using UCRSPH to target tumor cells. The CaO 2 facilitated the induction of Ca 2+ overload in cooperation with RuR which affected the SERCA and MCU in the ER and mitochondria, respectively [ 213 ]. (Reproduced with permission, copyright 2021, Wiley-VCH.) (d) Steps in active NP ER/BO−PDT nanoparticles synthesis. (e) Using NP ER/BO−PDT to inhibit tumor growth in a patient-derived osteosarcomas model. (f) NP ER/BO−PDT accumulated in the malignant bone tumors and were subsequently transported into the ER. NIR induced the ER stress to eliminate the tumor cells [ 214 ]. (Reproduced with permission, copyright 2022, Wiley-VCH.) Fig. 9

However, it is worth noting that UPR has a dual role. Under short-term stress, it can promote tumor cell apoptosis, but prolonged stress may activate pro-survival pathways, such as the IRE1-XBP1 axis, helping tumor cells adapt to ER stress and develop resistance [ 211 ]. Additionally, some tumors can alleviate ER stress by upregulating protein degradation pathways, such as ER-associated degradation, or by enhancing autophagy, which weakens the antitumor effects mediated by Toy [ 212 ]. Therefore, employing precise regulatory strategies targeting UPR pathways, such as combining XBP1 inhibitors or autophagy inhibitors, can effectively enhance the occurrence of LMP-induced tumor-killing effects and prevent adaptive resistance in tumors.

Calcium homeostasis imbalance

ER serves as a critical Ca 2+ reservoir within the cell. Certain factors, such as specific drugs and toxins, can interfere with the processes of Ca 2+ uptake or release in ER, leading to changes of Ca 2+ concentrations in ER. Disruption of Ca 2+ homeostasis affects the activity of many ER enzymes, including those involved in protein folding and processing, ultimately triggering ER stress [ 197 ]. In this context, Jiang et al. engineered a nanoplatform consisting of SA-CaO 2 and UCNPs-Ce6@RuR@mSiO 2 @PL-HA (UCRSPH) nanoparticles ( Fig. 9 b and c) [ 213 ]. Ruthenium red (RuR) was an inhibitor of calcium channel proteins (MCU). It restricted the expression of sarcoplasmic/ER calcium ATPase (SERCA) and MCU and therefore disrupted the normal transportation of cytosolic Ca 2+ to the ER, leading to Ca 2+ overload and disruption of Ca 2+ homeostasis in breast cancer cells. Furthermore , the incorporation of Ce6 and tumor tissue calcification allowed the nanoplatform to support both fluorescence imaging and computed tomography ( CT ) calcification imaging during tumor treatment.

Immunogenic cell death

When ER stress occurs, ROS production significantly contributes to cell death by releasing damage-associated molecular patterns (DAMPs), which ultimately cause ICD [ 214 , 215 ]. Unfortunately, the short half-lives and restricted diffusion of ROS render the induction of ICD less effective in certain tumors. To address this, Chen et al. synthesized nanodroplets (NDs) of a porphyrin derivative PMPS [ 216 ]. After intravenous injection, the NDs were cavitated by ultrasound, allowing the loaded sonosensitizer to infiltrate the tumor stroma and selectively accumulate in the ER. Further sonication led to the generation of substantial amounts of ROS in situ , subsequently provoking profound ER stress and ICD. Similarly, Zhang et al. performed photodynamic-immunotherapy using nanoparticles (NP ER/BO−PDT ) ( Fig. 9 d–f) [ 214 ]. Upon 808 nm NIR radiation, the nanoparticles fluoresced and generated ROS, producing additional DAMPs and inducing ICD. However, it is crucial to recognize that immune-suppressive elements within the tumor microenvironment, such as M2-type tumor-associated macrophages (TAMs), regulatory T cells, and myeloid-derived suppressor cells, can diminish the antitumor immune response triggered by ICD [ 217 , 218 ]. Thus, when developing ER stress-based immune-activating nanodrugs, it is essential to incorporate immune modulation strategies to counteract the negative impact of the tumor microenvironment and improve therapeutic effectiveness.

Endoplasmic reticulum-associated immune regulation

ER plays a multifaceted role in tumor immunity encompassing immune cell function, immune response regulation, and tumor immune evasion [ 219 , 220 ]. Firstly, ER participates in regulating the polarization of TAMs [ 221 ]. The ER stress-related IRE1-XBP1 pathway is a key regulator of TAM polarization. Inhibition of this pathway can reshape TAM metabolism, driving the repolarization of M2-TAMs into the pro-inflammatory M1 phenotype and enhancing its antitumor immune activity [ 222 ]. For example, Jiang et al. developed a nanoemulsion incorporating KIRA6 and α-tocopherol. KIRA6 effectively suppressed the IRE1-XBP1 pathway, while KIRA6 and α-tocopherol boosted glycolysis and inhibited fatty acid oxidation, successfully reprogramming M2-TAMs. This strategy not only suppressed the growth of tumor cells but also significantly enhanced the therapeutic efficacy of anti-PD-1 antibodies in the treatment of lung cancer [ 223 ].

Moreover, STING, an endogenous protein in the ER, initiates intracellular signaling cascades when activated, leading to an effective IFN-I-mediated immune response and immune activity modulation [ 224 , 225 ]. Consequently, many STING nanovaccines have been created to treat cancers. For example, Luo et al. employed their PC7A nanovaccine to achieve cytoplasmic delivery of tumor antigens to antigen presenting cells while simultaneously activating STING in ER, enhancing the therapeutic efficacy of anti-PD-1 antibody and improving immunotherapy outcomes in models of melanoma, colon cancer, and human papillomavirus-E6/E7 [ 226 ].

Golgi apparatus-targeting strategies

The GA is an essential membrane-bound organelle found close to the nucleus and consists of a series of flat cisternae [ 227 ]. The stacks of cisternae are polarized and play a significant role in intracellular protein processing, transport, and secretion [ 228 ]. Primary proteins essential for tumor development and progression depend on various modifications by GA, including glycosylation, sulfation, phosphorylation, and proteolytic cleavage [ 228 ]. In addition, the GA plays a role in numerous cellular metabolic and physiological activities related to tumors, such as endocytosis mediation and cell death regulation [ 229 ].

Golgi apparatus-targeting agents

Several GA-disturbing agents have been developed to date that directly change the structure of GA or attack protein trafficking pathways so as to induce apoptosis and kill tumors [ 230 ]. These include chondroitin sulfate (CS), retinoic acid (RA), six-cysteine (C 6 ) peptide, monensin, etc . ( Fig. 11 b) [ 231 , 232 ].

Liver cancer is an extremely consequential hepatic ailment characterized by the excessive production of extracellular matrix by hepatoma cells and activated hepatic stellate cells. The GA performs post-translational modifications on extracellular matrix components (e.g., collagen types I and III, proteoglycans, and fibronectin), enabling their secretion in a mature form, thereby playing a crucial role in tumorigenesis [ 233 ]. An earlier study found that nanomicelles of CS exhibited a strong binding affinity towards the GA in hepatic stellate cells [ 234 ]. Based on this, Li et al. constructed a prodrug nanoparticle system by synthesizing RA-conjugated CS (CS-RA) and loading with paclitaxel (PTX) ( Fig. 10 a) [ 235 ]. The prodrug nanoparticles demonstrated a tendency to collect within the GA of tumor cells and release RA in the acidic environment. This effectively disrupted the structure of the GA and hindered the expression of multiple metastasis-related proteins. In summary, targeting GA with CS and RA disrupts cellular activity and kills tumor cells. Fig. 10 Synthesis and therapeutic effects of GA-targeting nanosystems with the assistance of GA-targeting agents. (a) Schematic representation of the self-assembly process used to create the GA-targeting PTX-CS-RA prodrug [ 235 ]. (Reproduced with permission, copyright 2019, American Chemical Society.) (b) Structure of precursor peptide C 6 RVRRF 4 KY. (c) C 6 RVRRF 4 KY was self-assembled into furin-induced left-handed helical fibrils. (d) Left-handed helical fibrils were transported to the GA, where they self-assembled, disrupted membranes, and induced drug-resistant-free tumor cell death [ 237 ]. (Reproduced with permission, copyright 2021, American Chemical Society.) Fig. 10 Fig. 11 Structure design of (a) ER, (b) GA, and (c) proteasome-targeting agents. Fig. 11

Moreover, the C 6 can serve as a targeting moiety for GA by interacting with sulfhydryl-containing receptors in the GA lumen to establish disulfide linkages in the oxidizing environment [ 236 ]. For instance, Li et al. utilized C 6 as a key component in the design of a transformable peptide, C 6 RVRRF 4 KY, which could self-assemble into non-toxic nanoparticles in an aqueous medium. The nanoparticles precisely targeted the GA of tumor cells, disrupting the GA membrane, which led to cellular collapse and eventually induced tumor cell death ( Fig. 10 b–d) [ 237 ].

Golgi apparatus-mediated endocytosis

Endocytosis is an energy-dependent process through which extracellular materials are internalized via vesicles derived from CM. This process can be categorized into several pathways, including lysosome-mediated clathrin-dependent and GA-mediated caveolin-dependent endocytosis. By leveraging structural design, nanodrugs can preferentially enter cells via GA-mediated endocytosis, avoiding lysosomal degradation and significantly enhancing intracellular drug concentrations [ 238 ].

For example, Chu et al. developed PTX-cholesterol complex-loaded lecithin-chitosan nanoparticles (PTX-CH-loaded LCS-NPs). These nanoparticles efficiently penetrated cells through GA-mediated caveolae-dependent endocytosis. Meanwhile, PTX-CH-loaded LCS-NPs demonstrated excellent potential to induce apoptosis and effectively suppress tumor growth and metastasis in tumor-bearing mice [ 239 ]. Similarly, Huang et al. constructed Pleurotus tuber-regium (PTR)-conjugated SeNPs (PTR-SeNPs) for colorectal cancer treatment. PTR-SeNPs were internalized by tumor cells through caveolae-mediated endocytosis into GA. Once inside, PTR-SeNPs induced G2/M phase arrest and apoptosis in a dose- and time-dependent manner, leading to efficient tumor cell death [ 240 ]. However, there are significant differences in the activity of the GA-mediated caveolin-dependent endocytosis across different tumor types [ 241 ]. For instance, breast cancer and prostate cancer cells typically show high expression of caveolin, whereas high-grade malignant gliomas exhibit low or even absent caveolin expression, along with diminished or absent caveolin-dependent endocytosis [ 242 , 243 ]. This hampers the ability of nanodrugs to enter cells via this pathway, thus compromising therapeutic efficacy. Therefore, tailoring nanodrug designs and targeting strategies to specific tumor types is essential for optimizing endocytic efficiency and enhancing therapeutic outcomes.

Golgi apparatus-dependent cell death

Autophagy is essential to cell death and homeostasis. It recycles damaged organelles and denatured proteins that have reached their end of life. GA damage disrupts material transport, causing nutrient imbalance and autophagy-initiating stress [ 244 ]. Additionally, apoptosis is a controlled autonomous PCD mechanism, which destroys unnecessary or dangerous cells. GA injury can also disrupt intracellular signal transduction and affect apoptosis-regulatory factors, thereby activating apoptosis-related pathway [ 245 ].

Autophagosomes are formed and regulated by GA-related proteins, such as Golgin-245 and Golgi phosphoprotein 3 [ 246 ]. Ghaemi et al. developed Ag@ZnO nanoparticles, which exhibited the ability to generate ROS under ultraviolet light [ 247 ]. These ROS induced structural alterations of GA, transforming it from a compact, perinuclear organization into dispersed, vesicle-like structures in melanoma cells. This fragmentation of the GA disrupted cell cycle, promoting autophagy, and ultimately leading to the death of melanoma cells.

Furthermore, the oxidative stress in the GA induced by in situ ROS can trigger apoptosis. For example, Liu et al. created an aggregation-induced AIEgen-based photosensitizer (TPE-PyT-CPS) that targeted the GA and exerted a potent PDT effect [ 248 , 249 ]. TPE-PyT-CPS achieved GA through caveolin/raft-mediated endocytosis. Simultaneously, it generated significant amounts of singlet oxygen, fragmented GA, and cleaved GA-associated proteins (p115/GM130), thereby activating apoptotic pathways and killing tumor cells.

Proteasome-targeting strategies

The ubiquitin-proteasome system (UPS), which is primarily responsible for protein degradation, is a crucial regulatory pathway in eukaryotic cells [ 250 ]. The proteasome is a dynamic cellular machine consisting of two subcomplexes that form cylindrical structures: the core particle (CP, 20S) and regulatory particle (RP, 19S). The RP facilitates the ubiquitination of protein substrates, which are subsequently translocated into the closed cavity formed by the CP. Inside the CP, proteins are broken down into amino acids which are subsequently recycled by cells [ 251 ].

The proteasomes play a vital role in the regulation of intracellular homeostasis. On the one hand, the proteasomes take part in the degradation of abnormal proteins, thereby maintaining protein homeostasis within the cell [ 251 ]. On the other hand, proteasomes are involved various physiological processes, including epigenetic regulation, DNA synthesis, and repair [ 252 ].

Notably, proteasome dysfunction can contribute to the development of various human diseases, such as cancer [ 253 ]. Not surprisingly, there is a growing number of antitumor strategies that target proteasomes. For instance, proteolysis-targeting chimeras (PROTACs) can effectively activate the UPS, facilitating the recognition and degradation of target proteins within tumors, thereby suppressing tumor cell function [ 254 , 255 ]. Additionally, the proteasomes in tumor cells degrade abnormal proteins and regulate epigenetic repression, ultimately inhibiting the expression of tumor-related genes as well as hindering tumor initiation and progression [ 256 ].

Proteasome-targeting agents

PROTAC is a bifunctional molecule designed to facilitate targeted protein degradation. One end selectively binds to the target protein, often a pathogenic protein, while the other end binds to an E3 ubiquitin ligase. This proximity enables the E3 ubiquitin ligase to attach ubiquitin tags to the target protein. Once ubiquitinated, the target protein is recognized and degraded by the proteasome [ 257 ].Hence, the utilization of the PROTAC approach can achieve the precise degradation of certain proteins of interest in targeted tumor cells ( Fig. 11 c) [ 258 ]. For example, Song et al. developed a PROTAC system, called LipoSM-PROTAC, which is based on liposome self-assembly and incorporates FA to enhance its tumor-targeting capability ( Fig. 12 a–c) [ 257 ]. The system exhibited a robust ability to target tumors and degrade the corresponding proteins of interest, estrogen receptors. The PROTAC system effectively arrested the tumor cell cycle and induced apoptosis. Fig. 12 Schematic diagram showing proteasome-targeting strategies based on proteasomal structure and function. (a–c) Diagram of the novel Split-and-Mix Liposome PROTAC platform and folate-targeted protein degradation for tumor inhibition [ 257 ]. (Reproduced with permission, copyright 2023, American Chemical Society.) (d) Schematic diagram illustrated the action of a PROTAC-based protein degrader that targeted proteasome, depleted endogenous GPX4, and induced tumor cell ferroptosis. (e) Detailed illustration outlining how 401-TK-12 lipid NPs were degraded by ROS which selectively cleaved them at their dithioketal groups, thus releasing the dGPX4 [ 254 ]. (Reproduced with permission, copyright 2022, Wiley-VCH.) Fig. 12

However, it is noteworthy that compared to conventional drugs, PROTACs are typically larger molecules with limited membrane penetration capabilities, which may make it challenging for PROTACs to effectively enter tumor cells through the CM [ 259 ]. Nanoparticles, such as lipid nanoparticles and polymeric nanoparticles, can serve as effective delivery vehicles for PROTACs [ 254 ]. These nanocarriers, with their smaller particle sizes, can enhance the tumor cell penetration of PROTACs and protect them from metabolic degradation, thereby significantly improving drug delivery efficiency. For example, Luo et al. designed biodegradable PROTAC-based lipid nanoparticles (dGPX4@401-TK-12) to intracellularly deliver a GPX4 (the regulatory enzyme of ferroptosis) protein degrader, thereby inducing selective ferroptosis in tumor cells and achieving efficient tumor-killing effects ( Fig. 12 d and e) [ 254 ].

Proteasome-associated protein modulation

The p53 gene is widely acknowledged to be a suppressor of tumor genes. Mutant p53 (mutp53) drives uncontrolled tumor cell proliferation, fueling tumor initiation and progression. The degradation of mutp53 proteins via proteasomal mechanisms therefore offers a viable antitumor strategy. For example, Wang et al. designed AIE-Mit-TPP nanodrugs with AIE characteristics to induce proteasomal degradation of mutp53 proteins [ 260 ]. The authors also pointed out that the process was enhanced if autophagy was inhibited. Therefore, leveraging the protein-degrading capabilities of proteasomes to enhance the breakdown of tumor-associated pathogenic proteins represents a highly effective antitumor strategy in nanomedicine design.

Epigenetic repression alleviation

Epigenetic modifications, driven by mutations or dysregulation of DNA and histone modifications (such as methylation and acetylation), play a critical role in the development and progression of various cancers, including acute myeloid leukemia (AML). By effectively degrading methyltransferases and deacetylases, the proteasome can inhibit epigenetic modifications in tumor cells, thereby suppressing tumor progression [ 261 ].

For example, Kaundal et al. fabricated a polyethyleneimine (PEI)-conjugated human serum albumin (HSA) nanocarrier loaded with EZH2-specific siRNA (HSANPs-PEI@EZH2siRNA), designed to target EZH2-expressing genes in AML [ 256 ]. This nanocarrier effectively enhanced EZH2 gene silencing, directly inhibiting the expression of c-Myb (AML-responsive transcription factors) and polycomb proteins EZH2 (epigenetic regulators involved in gene repression) via the proteasomal degradation pathway. In a xenograft AML mouse model, treatment with this nanocarrier resulted in a reduction in splenomegaly and overall retardation of AML progression. However, it is crucial to recognize that the restoration of epigenetic modifications is a complex process governed by multiple factors. Solely targeting proteasomal regulation, such as the degradation of EZH2, may not be sufficient to completely suppress the malignant traits of tumor cells. This is because epigenetic modifications involve a variety of enzymes, non-coding RNAs, and chromatin-associated factors, which may employ compensatory mechanisms to restore the malignant characteristics of tumor cells [ 262 ]. Such restoration can undermine treatment effectiveness and contribute to tumor progression.

Brief summary and prospect

The design of most current organelle-targeting nanomedicines predominantly focuses on individual organelles. This approach offers the advantages of a relatively straightforward design process, facilitating the efficient development of nanomedicines that achieve desired outcomes. However, from the perspective of organelle features, there are still nanodrugs directed at certain organelles that remain underexplored [ 263 , 264 ]. Developing nanomedicines targeting ER, GA, proteasomes, ribosomes, and autophagosomes presents an opportunity to achieve improved therapeutic effects by leveraging precise structural targeting and function regulation of specific organelles. This progress will likely depend on the application of innovative materials and the design of novel nanostructures. More importantly, this “linear” design strategy relies on an overly simplified understanding of cellular physiological processes [ 17 ]. Such simplification, which primarily considers “one-to-one” interactions, results in a limited understanding of the biological effects of nanostructures. Moreover, it neglects the synergistic or antagonistic interactions between the targeted organelles and other organelles, potentially missing opportunities to further enhance the therapeutic efficacy of these nanomedicines. Sections 3 , 4 delve into these issues in greater detail.

Nanostructure design for organelle escape

As discussed in Section 2.7 , achieving the therapeutic goal of targeting specific organelles within tumor cells requires nanodrugs with structures that can bind to the desired organelles and facilitate the effective release of their active components. Additionally, these nanodrugs must navigate and overcome various obstacles encountered en route to their targets.

Different organelles within a cell function as interconnected entities. Prior to reaching the targeted organelle, the nanodrugs must be shielded from premature degradation and deactivation within the intracellular environment, such as by lysosomes and proteasomes [ 269 ]. In addition, it is important to recognize that the incorrect delivery of drugs can undermine the efficiency of the drug delivery process, and potentially lead to genotoxicity [ 270 ]. Furthermore, the process of organelle escape serves as a “relay station” for nanomedicines, facilitating precise drug enrichment within specific organelles (e.g., lysosomes), thus aiding the transportation of drugs to the targeted organelle [ 271 ]. This can greatly reduce dispersion of the nanodrugs within the cytoplasm thus enhancing the efficacy of the organelle-targeting process.

In this section, we review three organelle-escaping strategies for precise tumor therapy, encompassing the lysosomal escape mechanism (prevalent) [ 272 ], as well as nuclear and proteasome escape mechanisms (less common) ( Fig. 13 ) [ 273 ]. This aims to offer invaluable guidance to materials scientists, assisting them in designing the structural features necessary for creating precise and efficient nanodrugs from a more comprehensive perspective ( Table 2 ). Fig. 13 Schematic illustration of organelle-escaping nanodrugs in precise tumor therapy. The red arrows represent the final escape route of nanodrugs. (Created with BioRender.com.) Fig. 13 Table 2 Summary of recent articles on organelle escape in precise tumor therapy. Table 2 Organelle Mechanism of action Form Structure Preparation and functionalization Diameter (nm) Cell lines Animal model Therapy Ref. Lysosome Proton sponge effect Nanoplatforms BP-DOX@Gd/(DOPA)4-PEG-TL VDW, CC, CI, BF a 150–250 MCF-7 Subcutaneous xenograft tumor models PTT; Chemotherapy [ 282 ] Lysosomal membrane fusion Nanosystems PB@LC/D/siR EA, CC, BF 92.7 PCa BABL/c nude mouse BmCRPC model Chemotherapy [ 288 ] Lysosomal membrane disruption Nanofibers; Nanoparticles Cell-penetrating transformable peptide nanoparticles VDW, CC, BF 15.35 (pH = 7.4) A549 Athymic mice bearing A549 flank tumors Chemotherapy [ 173 ] Nanoparticles CuS-RNP@PEI HI, CC, BF 65 CNE-2 CNE-2 tumor-bearing nu/nu nude mice PDT; Gene therapy [ 312 ] Photochemical internalization Nanocarriers Glycosylated nanocarriers co-loaded with Ce6 and GemE VDW, HI, HGI 10–20 MB49-PSA C57BL/6 mice orthotopic bladder cancer model PDT; Chemotherapy [ 296 ] Nucleus Nuclear envelope budding Torsin NA NA NA NA NA NA [ 302 ] Proteasome Inhibit UPS protein degradation pathway Nanoparticles CuSCDB@MMT7 EA, BF 200 MCF-7 4T-1 L929 Thp-1 RAW 264.7 4T1 tumor-bearing BALB/c mice PTT [ 305 ] Nanoparticles BCMA-BTZ-NPs HI, PE, CC, BF 168 ± 15 Bone marrow mononuclear cells CD138 + MM monocyte-derived dendritic cells naive T cells 1S MM plasmacytoma bearing NSG mice Chemotherapy [ 311 ] a Abbreviation in the table: EA: electrostatic adsorption, VDW: van der Waals forces, HI: hydrophobic interaction, PE: physical encapsulation, CC: covalent coupling, RR: redox reaction, CI: coordination interaction, HGI: host-guest interaction, BF: biomimetic functionalization, GEF: genetic engineering functionalization.

Lysosome-escaping strategies

Often referred to be cellular “recycling bins”, lysosomes act as degradation compartments for most biosynthetic products. This function is carried out through their lumen, which contains a wide array of destructive enzymes, such as hydrolases. Many nanodrugs struggle to achieve satisfactory efficacy due to degradation within intracellular lysosomes. Therefore, to accomplish the targeting of specific organelles, such as mitochondria, one of the first steps is to modify the nanoparticles to ensure they can escape from lysosomes.

Lysosome escape refers to a procedure by which molecules or particles can avoid degradation by lysosomes after being endocytosed by cells (thus allowing them to reach their organelle target where they can release their therapeutic cargo) [ 274 ]. The lysosome escape of nanoparticles can therefore significantly enhance their precise delivery to their targets, while preventing the drug from dispersing throughout the cytoplasm (which would probably reduce its therapeutic effect) [ 275 , 276 ]. The design of nanodrugs has advanced to ensure precise regulation of lysosomal membrane structures, thereby altering their permeability, disrupting compartmentalization, and facilitating lysosomal escape. Specific strategies for lysosome escape, including the proton sponge effect, membrane fusion, and membrane disruption within lysosomes, will be elaborated in the subsequent sections [ 277 ].

Proton sponge effect

The proton sponge effect was hypothesized in the late 1990s. This concept suggests that certain cationic polymers can induce osmotic swelling and exacerbate lysosomal acidification through proton sponge effect. This process ultimately leads to lysosomal lysis and the subsequent release of their contents [ 278 ]. Research has shown that achieving the proton sponge effect requires appropriate chemical modifications of nanodrugs, such as introducing protonatable amine fractions or disulphide bonds. Once inside acidic lysosomes, these chemically modified nanodrugs keep the proton pump V-ATPase continuously active, promoting chloride ion exchange and enhancing water infiltration. This sequence of events induces osmotic swelling, ultimately resulting in proton sponge effect [ 269 , 279 ].

Li et al. designed various biodegradable CO 2 -derivative cationic poly (vinyl cyclohexene carbonates) (CPCHCs) as gene vectors to create an antitumor siRNA therapy aimed at osteosarcoma treatment [ 280 ]. The CPCHCs contained numerous tertiary amine groups, which were essential for generating CPCHC-induced proton sponge effect to help lysosome escape of the siRNA. Similarly, Kanjilal et al. reported that nanogels with disulphide bonds experience enhanced lysosomal escape due to their strong interaction with lysosomal thiols [ 281 ]. Furthermore, a BP-DOX@Gd/(DOPA) 4 -PEG-TL nanoplatform was reported as well to exhibit lysosome escape, attributed to the proton sponge effect. In this case, it was the buffering ability of the modified Gd 3+ -polyphenol network that led to lysosome rupture and nanodrug release [ 282 ]. Other studies have also shown that the proton sponge effect can be employed to avoid lysosome-induced drug deactivation and degradation [ 283 , 284 ].

Notably, chloroquine (CQ), a weakly basic drug containing basic functional groups in its molecular structure, exhibits distinct behavior in the acidic environment of lysosomes [ 285 ]. Upon entering lysosomes, CQ undergoes protonation, resulting in the formation of positively charged CQ ions [ 286 ]. Due to their positive charge, these ions are unable to easily traverse the lysosomal membrane, resulting in their accumulation within the lysosomes. This accumulation induces a proton sponge effect, ultimately impairing lysosomal function. As a consequence, lysosomal rupture occurs, leading to the release of its contents and facilitating lysosome escape [ 285 , 286 ]. For instance, Gao et al. developed a hyaluronan (HA) nanogel co-loaded with CQ and cisplatin (HA/Cis/CQ nanogel) [ 287 ]. Compared to HA/Cis nanogels, which were solely loaded with cisplatin, the HA/Cis/CQ nanogels significantly enhanced lysosome escape of cisplatin and improved antitumor efficacy while reducing associated side effects in a triple-negative breast cancer model. Mechanistic studies revealed that the co-delivery of CQ not only increased LMP but also inhibited lysosomal autophagy, thereby promoting lysosomal instability, facilitating cisplatin escape, and tumor killing.

Lysosomal membrane fusion

Membrane fusion is the process by which two closely apposed lipid bilayers merge to form a single bilayer. Liposome-nanocomposite systems can fuse with the lipid components of intracellular membrane structures, thereby promoting lysosome escape.

For example, Chen et al. developed lipoic acid-containing PB@LC/D/siR nanoparticles to target prostate cancer cells and deliver docetaxel and sterol regulatory element-binding protein 1 siRNA [ 288 ]. In this case, lipoic acid nanoparticles were used to be internalized by prostate cancer cells and escape from the lysosomes through clathrin-mediated endocytosis. Subsequently, the PB@LC/D/siR nanoparticles successfully delivered their therapeutic contents, including docetaxel and sterol regulatory element-binding protein 1 siRNA to prostate cancer cells [ 288 , 289 ]. This resulted in significant downregulation of SREBP1 and suppression of cancer cell growth. Therefore, membrane fusion is a promising potential strategy for lysosome escape.

Lysosomal membrane disruption

Recently, a large number of nanodrugs have been developed that leverage various endogenous and exogenous stimuli to disrupt lysosomal membranes, thereby facilitating lysosome escape [ 290 ]. One of the most commonly used endogenous stimuli is pH [ 291 ]. Additionally, exogenous stimuli include various physical methods (such as ultrasound, electroporation, and light), as well as chemical methods (such as membrane-active peptides, antimicrobial peptides, and chemical drugs like digoxin) [ 267 , 292 ].

pH

The change in lysosomal pH, which induces conformational alterations in nanodrugs, is a common endogenous factor that triggers lysosomal membrane disruption [ 291 ]. For instance, Baehr et al. developed a cell-penetrating transformable peptide nanoparticle (CPTNP) consisting of peptide amphiphiles which self-assembled into nanoparticles ( Fig. 14 ) [ 173 ]. The CPTNPs were found to co-localize with lysosome and change their conformation due to the pH of the lysosomal content, thus forming nanofibrils. The subsequent formation of nanofibrils disrupted the lysosome membrane, enabling the entrapped cisplatin to escape from the lysosomes into the cytosol. Eventually, the CPTNP-cisplatin synergism led to cell death. Fig. 14 Utilization of CPTNPs for the tumor cell internalization and subsequent cisplatin release via LMP. (a) CPTNPs transformed under pH changes, forming nanofibrils that disrupted lysosomal membranes. (b) FITC-dextran was sequestered into lysosomes; LMP caused loss of punctate patterns and increased fluorescence. (c) Assay results with varying FITC-dextran concentrations. (d) Galectin-1 puncta assays demonstrated fibril-induced LMP. (e) Galectin puncta assay: cytosolic galectin-1 indicated no LMP, while punctate distribution indicated LMP induction. (f) Galectin-1-stained tumors with CPTNP-FF or PBS; white arrows highlighted puncta, confirming CPTNP-induced LMP in vivo . (g) TEM images of A549 cells treated with CPTNPs or PBS; red arrows marked nanofibrils [ 173 ]. (Reproduced with permission, copyright 2021, Elsevier Ltd.) Fig. 14

Ultrasound

Ultrasound can increase the permeability of cellular membrane structures, thereby encouraging lysosomal membrane rupture and facilitating the escape of nanodrugs from lysosomes. For example, Cheng et al. created in situ self-assembling polymer-peptide conjugate PEG-tk-(P18)KLAK (PTPK) nanoparticles capable of deep tissue penetration [ 293 ]. The synergistic effect of ultrasound on membrane permeability further boosted the endocytosis of PTPK nanoparticles and facilitated more efficient lysosome escape via lysosomal membrane breakdown, hence improving therapeutic efficacy. Owing to the significant tissue penetration depth and spatial precision of ultrasound, PTPK nanoparticles demonstrated enhanced tumor-suppressive effects in an in situ pancreatic tumor model.

Photochemical internalization

Photochemical internalization (PCI) is a process that utilizes light to trigger chemical reactions, generating reactive photochemical products such as ROS or azide radicals. These products disrupt the lysosomal membrane, enabling the release of therapeutic agents that were previously trapped within the lysosomes. This method enables the controlled release of various antitumor drugs into the cytoplasm, where they can exert their maximum therapeutic effect [ 294 ]. Notably, PCI can also release other substances, such as hydrolases, from the lysosome into the cytoplasm. This can cause inflammation and other forms of cellular stress, which may further enhance the tumor-killing effect [ 294 ].

Theodossiou et al. prepared porphyrin-β-cyclodextrin nanoconjugates loaded with tamoxifen (a well-known drug used to treat breast cancer) [ 295 ]. They likened the nanoconjugates to “Trojan horses” because they facilitated the release of drugs into the cytosol of the tumor cells. In this case, the applied radiation was absorbed by the porphyrin which expedited the rupture of the lysosomal membrane and high-concentration release of the tamoxifen into the tumor cells via PCI. Similarly, Panagiotakis et al. synthesized nanoconjugates of β-cyclodextrin with various triphenylporphyrins (which are highly hydrophobic) [ 296 ]. These nanoconjugates were subsequently used to introduce small antitumor drug molecules into MCF-7 breast cancer cells, wherein the drug was released via PCI upon exposure to light.

Furthermore, the effectiveness of PCI is often limited by low penetration of light and drug in targeted tissues. To overcome such problems, Sun et al. recently developed a novel approach to improve the PCI process ( Fig. 15 ) [ 297 ]. This tumor-targeting glycosylated nanocarrier was fabricated, co-loaded with Ce6 and gemcitabine elailate (GemE). Using a miniaturized, implantable, wireless-powered light-emitting diode (LED) as the light source, the system achieved efficient photodynamic-chemotherapy. The LED continuously provided low-intensity PDT at 1 mW/cm 2 , inducing a PCI effect that facilitated nanodrugs escape from lysosomes into the cytoplasm, thereby enhancing therapeutic efficacy. Notably, this approach significantly reduced in situ tumor burden in mice, achieving a 90 % therapeutic effect compared to 35 % in the control group, highlighting a potential novel treatment strategy for bladder cancer [ 298 ]. Fig. 15 Application of drug-loaded nanocarriers with wireless micro-LEDs for bladder cancer treatment via PCI effect. (a) Glycosylated nanocarriers loaded with Ce6 and GemE were fabricated. (b) TEM and high-resolution TEM images of 50GCG nanocarriers. (c) Nanocarriers facilitated synergistic PDT and chemotherapy via the PCI effect. (d–e) Schematic representation of a novel approach for the orthotopic bladder cancer treatment. (f–g) The structure of the wireless PDT device. (h) The PDT device was positioned adjacent to the mouse bladder and anchored to abdominal muscles. (i) The activated device was photographed after wound closure. (j) A CT scan highlighted the implanted wireless device (white dotted square). (k) A magnified CT scan showed the device (pink dotted line) above the inflated bladder (yellow dotted line) [ 297 ]. (Reproduced with permission, copyright 2022, Wiley-VCH.) Fig. 15

Nucleus-escaping strategies

The intracellular transportation of nanodrugs is quite a complicated process. If nanodrugs inadvertently enter the nucleus, they may compromise the accuracy of the drug delivery process and diminish the overall therapeutic effectiveness. Moreover, the inappropriate accumulation of nanodrugs in the nucleus could have unexpected side effects, e.g., genetic toxicity, metabolic toxicity, signaling disorder, etc [ 299 , 300 ].

However, no nanodrug has so far been specifically designed to escape the nucleus (such development would clearly improve the precision of the organelle targeting process). Nevertheless, several studies on viral escape from the nucleus are inspiring and highly illuminating, and may provide new ideas for further improving the design of precise organelle-targeting drugs. As such, it is worth mentioning them briefly here.

Herpesviruses are thought to be able to escape from the nucleus via an envelopment-development-re-envelopment process, which involves two kinds of viral proteins. One viral protein is involved with kinase phosphorylating and dissolving the nuclear lamina. The other (conserved) nuclear membrane-associated protein participates in the primary envelopment process [ 301 ]. Another study has indicated that nucleus escape can be triggered by the assembly of large viral capsids inside the nucleus [ 302 ]. This process is referred to “NE budding” and is thought to involve the endogenous protein Torsin ( Fig. 16 ). Hopefully, the proteins and processes mentioned above may provide inspiration for the future development of nanodrugs capable of nucleus escape. Fig. 16 Schematic illustration of nucleus-escaping potential pathway in precise tumor therapy. (Created with BioRender.com.) Fig. 16

Proteasome-escaping strategies

As a highly regulated intracellular protein degradation mechanism, the UPS is a key pathway for the selective degradation of specific proteins, crucial for the selective elimination of particular proteins, including those that are short-lived, misfolded, damaged, or present in excess within the cell [ 303 ]. Research indicated that aberrant activation of the UPS may significantly contribute to several malignancies by degrading tumor suppressor proteins, including IκBα, p27, p21, and p53, as well as cell cycle checkpoint inhibitors, resulting in accelerated cell proliferation and tumorigenesis [ 304 , 305 ]. Constructing effective nanodrugs that help these proteins escape proteasomal degradation may suppress abnormal activation in cancer, providing novel approaches for precise tumor therapy ( Fig. 17 a). Fig. 17 Nanomedicine strategies for precise tumor therapy through escaping proteasomal degradation pathways. (a) Schematic illustration of proteasome escape pathway in precise tumor therapy. (Created with BioRender.com.) (b) Proteasome inhibitor-encapsulated CuS/carbon dots nanocomposites enhanced PTT treatment by stabilizing substrates in the proteasomal degradation pathway [ 305 ]. (Reproduced with permission, copyright 2020, ACS Publication.) (c) BCMA-BTZ-NPs inhibited proteasomal degradation, causing toxic protein accumulation, apoptosis, enhanced ICD, and tumor-specific cytotoxicity in resistant cells [ 311 ]. (Reproduced with permission, copyright 2023, Nature Portfolio.) Fig. 17

Current studies suggest that proteasome inhibitors can effectively safeguard tumor suppressor proteins from degradation induced by the UPS. Bortezomib (BTZ), the first FDA-sanctioned proteasome inhibitor, has demonstrated significant antitumor activity in multiple types of tumors [ 306 , 307 ]. By protecting tumor-suppressing proteins from degradation via the UPS, BTZ inhibits the proliferation and metastasis of tumor cells. Based on this mechanism, Yu et al. constructed BTZ -encapsulated hollow-structured CuS nanoparticles integrated with carbon dots (CuSCDs). This system exhibited excellent photothermal conversion efficiency at 808 nm laser irradiation. The synergistic effect of PTT and BTZ not only prevented UPS-mediated protein degradation, but also, via photothermal-induced effects, markedly suppressed tumor cell proliferation and metastasis ( Fig. 17 b) [ 305 ].

Furthermore, as a proteasome inhibitor, BTZ facilitates the accumulation of deleterious proteins in cells by obstructing proteasome function, hence activating apoptotic pathways, inducing cell cycle arrest, and finally resulting in cell death [ 307 , 308 ]. Based on this mechanism, BTZ has also been extensively applied in the treatment of multiple myeloma (MM), an incurable malignancy of plasma cells often accompanied by severe immune deficiency and dysfunction [ 309 , 310 ]. For example, Dutta et al. advanced nanoparticles that contained BTZ and were functionalized on their surface with BCMA antibodies (BCMA-BTZ-NPs). In BTZ-resistant MM models, BCMA-BTZ-NP exhibited markedly superior proteasome inhibition. In a murine xenograft model, BCMA-BTZ-NPs preferentially localized at the tumor site, reduced off-target toxicity, and showed significant benefits in surmounting drug resistance, presenting novel treatment strategies for MM patients ( Fig. 17 c) [ 311 ].

Brief summary and prospect

In the design of organelle-targeting nanodrugs, researchers need to carefully consider the interactions among different organelles, including the lysosomes, nucleus, and proteasomes. These interactions necessitate that nanodrugs must not only possess the ability to target specific organelles but also incorporate structural elements that prevent damage or misrecognition by other organelles. By embedding these characteristics into nanodrug design, the precision of organelle targeting is significantly enhanced, thereby improving the efficacy of tumor therapy.

These studies suggest that nanodrugs should be designed from a more holistic perspective, rather than focusing solely on targeting a single organelle, in order to achieve higher therapeutic efficiency. Notably, as a complex system, the intricate relationships among different organelles still involve numerous interactions that have not been fully addressed in organelle-targeting drug design. For example, previous designs have often concentrated on the effect of lysosomes on nanodrug targeting, neglecting the potential barriers lysosomes may present to nanodrugs targeting other organelles [ 272 ].

Considering the high degradability of lysosomes, the genetic toxicity of the nucleus, and the protein degradation capabilities of the proteasomes, there are substantial opportunities to refine nanodrug structures by minimizing interference with the aforementioned organelles. This can be achieved by integrating the critical characteristics of lysosomes, the nucleus, and the proteasomes into the design process.

Nanostructure design for multi-organelle collaboration

In the booming development of precision medicine, nanomedicine has emerged as a pivotal force in tumor treatment. Its primary advantage is the precise delivery of drugs to specific organelles, which significantly enhances therapeutic efficacy while minimizing side effects. As research into cellular physiological mechanisms progresses, the role of inter-organelle interactions and collaborations in maintaining cellular homeostasis and in the development of diseases has become increasingly prominent. In this context, we present an overview of current biological research on organelle interactions and examine nanostructure designs aimed at facilitating multi-organelle collaboration in tumor therapy. This includes mechanisms of inter-organelle interactions, multi-organelle targeting strategies, and practical application cases, while also analyzing the limitations in current research, providing a comprehensive and systematic reference for the further development of this field.

Interaction and collaboration among different organelles

The maintenance of cellular homeostasis and function depends on various organelles efficiently collaborating and interacting with one another. Although each organelle performs specific cellular processes, their synchronous operation is essential for cells as it allows them to adapt to environmental changes and survive [ 313 , 314 ]. The coordination among organelles is facilitated by various complex communication networks, including signaling pathways and membrane contact sites (MCSs) [ 315 ]. The networks regulate metabolic and physiological functions and mediate responses to cellular stress [ 316 ]. Dysregulation of multi-organelle interactions can result in the onset of diseases, such as cancer and neurodegenerative disorders. The following sections provide a detailed discussion of the physiological processes underlying multi-organelle interactions and collaborations, focusing on their mechanisms and functions, as well as the pathological features associated with their dysregulation ( Fig. 18 ). Fig. 18 Schematic illustration of organelle interaction and communication. (Created with BioRender.com.) Fig. 18

Mechanisms of organelle interaction

Signal molecules

Signal molecules are pivotal in inter-organelle interactions, as they regulate the production and release of signaling molecules [ 317 ]. A variety of proteins and ions are now known to be involved in organelle signal transduction, such as Ca 2+ , ROS, and membrane proteins, etc . Ca 2+ , as an essential messenger molecule, is central to the communication that occurs between the ER and mitochondria. For example, Ca 2+ transfer helps regulate organelle stress responses (such as ER stress and mitochondrial oxidative stress), ATP production and apoptosis, showcasing how crucial these interactions are to cellular survival [ 197 ].

Furthermore, mitochondria are one of the primary sources of ROS, particularly during OXPHOS. When mitochondria experience stress or dysfunction, increased ROS production can serve as a signal molecular to the nucleus [ 318 ]. ROS activate transcription factors like nuclear factor kappa B or AP-1, which in turn upregulate genes involved in antioxidant defense, such as superoxide dismutase and catalase. These genes help the cell to mitigate oxidative damage, thereby maintaining cellular homeostasis [ 319 ].

Moreover, a common feature of all mammalian organelles is that they are surrounded by membranes. These membranes serve not only as structural barriers but also as reservoirs of signaling molecules, playing an active role in subcellular interaction and communication [ 320 , 321 ]. For example, mitofusins (MFN-1 and MFN-2) are involved in mitochondrial fusion, a process that is essential for mitochondrial quality control and energy distribution in cells [ 322 ]. MFNs mediate the tethering and fusion of mitochondria to the ER, a crucial interaction that supports Ca 2+ homeostasis and lipid transfer [ 323 ].

Membrane contact sites

MCSs among organelles like mitochondrion-associated membranes (MAMs) play a pivotal role in multi-organelle interaction by facilitating the exchange of ions, lipids, and proteins [ 324 ]. Notably, MAMs mediate crucial processes such as the transfer of Ca 2+ between the ER and mitochondria [ 325 ]. These transfer processes are regulated by several key proteins, including inositol 1,4,5-trisphosphate receptor (IP3R), VDACs, and glucose-regulated protein 75, all of which are crucial for energy production and PCD [ 326 , 327 ].

MAMs also play a key role in lipid metabolism by mediating the transfer of lipids between the ER and mitochondria ( Fig. 19 a) [ 328 , 329 ]. The ER is responsible for synthesizing a variety of lipids, including phospholipids, which are critical components of cellular membranes. Specific lipids, like phosphatidylserine, are synthesized in the ER and then transferred to the mitochondria via MAMs. Inside the mitochondria, the phosphatidylserine is converted into phosphatidylethanolamine, an essential lipid for mitochondrial membrane integrity and function [ 330 , 331 ]. MAMs also facilitate the exchange of cholesterol and other lipids necessary for mitochondrial membrane biogenesis and the production of steroid through oxysterol-binding proteins and oxysterol-binding proteins ( Fig. 19 b–d) [ 332 , 333 ]. Fig. 19 (a) Lipids mediated inter-organelle interactions, with a schematic network highlighting key lipids involved in signaling pathways. Gray shading and line thickness reflected the level of understanding of each interaction, with darker, thicker lines indicating better-understood interactions, such as between mitochondria and ER [ 329 ]. (Reproduced with permission, copyright 2024, Elsevier Ltd.) (b–d) MCSs and their respective functions. (b) ER-mitochondrion contact sites regulated lipid transport, mitochondrial dynamics, Ca 2+ homeostasis, ROS signaling, autophagy, and organelle trafficking. (c) ER-lysosome contact sites controlled lysosome positioning, maturation, membrane integrity, and material exchange. (d) Membrane contact sites in the ER-ERES-Golgi system facilitated secretory protein trafficking [ 333 ]. (Reproduced with permission, copyright 2024, Science China Press.) Fig. 19

Functions of organelle interaction

Organelle interaction is essential for regulating intracellular transport and metabolism. For instance, the contact sites between the ER and mitochondria are crucial for phospholipid synthesis, which maintains the integrity and function of the mitochondrial membrane [ 334 ]. Similarly, ER-lysosome interactions regulate cholesterol metabolism, highlighting how communication between these organelles supports lipid homeostasis [ 335 ]. In addition, organelle interactions also influence the dynamic morphology of organelles, particularly the mitochondria [ 336 ]. For instance, the interaction between ER and lysosomes also facilitates the regulation of mitochondrial fission and fusion, which is essential for maintaining mitochondrial function [ 336 ].

Furthermore, interactions among different organelles are vital for cellular responses to both internal and external stressors. For instance, the interaction between lysosomes and mitochondria contributes to cellular responses to ER stress and the UPR, which are essential for mitigating stress-related damage [ 195 , 337 ]. Similarly, in response to environmental stress, such as nutrient deprivation, organelle interaction plays a pivotal role in ensuring cellular adaptation. For example, lysosomes and autophagosomes increase activity to degrade cellular components and recycle nutrients, which are vital for cell survival under such conditions [ 338 ]. External stressors, including chemicals, can disrupt organelle interactions by altering the shape or mechanical contacts at membrane sites, significantly impacting cellular signaling and homeostasis [ 339 ].

Dysregulated organelle interaction and tumor development

Dysregulated organelle interaction is associated with several diseases, including cancer, neurodegenerative diseases, and metabolic disorders [ 197 ]. Abnormal expression of MCSs among organelles and impaired signaling pathways play critical roles in tumor progression and metastasis [ 197 , 340 ]. For instance, MAM proteins, such as IP3Rs, which mediate interactions between the mitochondria and ER, are overexpressed in various cancers, including breast cancer and glioblastoma. This overexpression promotes the efficient transfer of Ca 2+ from the ER to mitochondria, enhancing mitochondrial enzyme activity and ATP production [ 341 ]. Moreover, Ca 2+ regulates cell cycle proteins (e.g., Cyclin D) and activates proliferation-related signaling pathways, such as the PI3K-AKT pathway, further driving tumor growth [ 197 ]. Additionally, elevated Ca 2+ levels enhance lysosomal exocytosis, facilitating the degradation of the extracellular matrix and enabling tumor cells to invade nearby tissues and metastasize to distant organs [ 342 , 343 ]. In conclusion, organelle interaction and collaboration are essential for maintaining cellular homeostasis, regulating metabolism, and facilitating stress adaptation. Disruptions in these interactions can drive disease progression, particularly in cancer ( Table 3 ). Table 3 Summary of recent articles on multi-organelle targeting in precise tumor therapy. Table 3 Organelles Mechanism of action Form Structure Preparation and functionalization Diameter (nm) Cell lines Animal model Therapy Ref. Mitochondrion and ER Calcium homeostasis imbalance Nanoparticles EMT-NPs HI, CC a 91 A549 A549-tumor-bearing mice Chemotherapy [ 353 ] Liposome A biomineralized liposome loaded with DHA PE, CI, BF 146.27 ± 1.86 A549 A549-luc HUVEC Orthotropic A549-luc-tumor-bearing BALB/c nude mice Lung cancer ferroptosis therapy [ 352 ] Mitochondrial network fusion regulation Nanomedicine MiND NPs EA, HI, PE 164 ± 21 MDA-MB-231 BT-549 NA Chemotherapy [ 354 ] Immune microenvironment regulation Nanomedicine GCT@CM NPs HI, CI, BF 210 B16 L929 RAW 264.7 Dendritic cells B16-tumor-bearing mice Immunotherapy; Chemotherapy [ 210 ] Self-assembled nanoparticles (Nig + DAC) @HmA HI, PE, CI 218.4 ± 3.2 MB49 4T1 MB49 tumor-bearing mice Immunotherapy [ 266 ] Mitochondrion and lysosome Calcium homeostasis imbalance Nanoparticles DSF-loaded Ca 2+ /Cu 2+ dual-ions “nano trap” PE, CC, CI, BF 100 4T1 4T1-tumor-bearing BALB/c mice Ion-interference therapy [ 368 ] Nano-CaCO 3 CaCO 3 @TCPP/CAR (CTC) PE 130 4T1 4T1-tumor-bearing BALB/c mice Ion interference therapy [ 369 ] Structure targeting agents Nano-prodrug DM NPs VDW, HI, CC, GEF 84 CT-26 CT-26 Mito-FAP NA PTT; PDT [ 365 ] Lysosomal-mitochondrion axis modulation RBC-derived vesicles Dox-gluRDVs CC, BF NA MES-SAMES-SA/Dx5 MES-SA/Dx5 tumor-bearing BALB/c nude mice Chemotherapy [ 366 ] Nanoparticles 131 I-EM@ALA PE, CC, BF 154.8 ± 2.8 4T1 4T1-tumor-bearing BALB/c mice PDT; Radiotherapy [ 367 ] ER and GA Golgi-ER transport system Nanoparticles GENPs PE, BF, GEF 136.7 B16-F10 C57BL/6J mice Immunotherapy; Chemotherapy [ 232 ] Nanoplexes EhCv/siRNA NPs EA, BF 188.2 ± 2.6 MCF-7 HepG2 HT-1080 A549 MCF-7-tumor-bearing-BALB/c mice NA [ 377 ] Structure targeting agents Twisted nanofibrils; flat nanoribbons In situ self-sorting peptide assemblies within living cells CC, RR, HI, BF 35 width 11.6–156.2 HeLa A549 HEK293 NA NA [ 375 ] Mitochondrion and nucleus Nanomaterials NanoparticlesCBNs-Pluronic F127-DOX (CPD) NP-DBD HI, CC, BF 100 A549 4T1 4T1-tumor-bearing mice PDT; PTT [ 387 ] PE 68 4T1 4T1-tumor-bearing BALB/c mice Chemotherapy [ 142 ] Triple Organelles Mitochondrion, nucleus, and lysosome Nanocages GDMCN2 system PE, CC, CI, BF 37 PANC-1/GEM PANC-1/GEM-tumor-bearing BALB/c nude mice Sonodynamic therapy [ 404 ] Mitochondrion, ER, and GA Nanoplatform BMA EF PE, CC, RR, CI, BF ∼200 4T1 MCF-10A 4T1-bearing BALB/c mice and BALB/c nude mice PTT; Immunotherapy [ 394 ] Mitochondrion, ER and nucleus Nanoparticles COMBO VDW, CI 97.85 ± 0.42 4T1 4T1-tumor bearing mice Chemotherapy [ 399 ] a Abbreviation in the table: EA: electrostatic adsorption, VDW: van der Waals forces, HI: hydrophobic interaction, PE: physical encapsulation, CC: covalent coupling, RR: redox reaction, CI: coordination interaction, HGI: host-guest interaction, BF: biomimetic functionalization, GEF: genetic engineering functionalization.

Multiple organelle targeting strategies

Mitochondrion and endoplasmic reticulum targeting strategies

Over the past few decades, several studies have demonstrated that the interactions and communications between mitochondria and ER profoundly influence cellular functions such as material transport [ 344 ]. Mitochondria are pivotal in cellular metabolism, serving as the locus for ATP generation via OXPHOS, tricarboxylic acid cycle, and other metabolic processes [ 333 ]. The ER is a complex network characterized by a substantial membrane surface area [ 333 ]. Within the ER, numerous morphological regions, such as tubules and sheets, interact with various organelles, thereby facilitating a diverse range of functions [ 333 ].

The interaction between mitochondria and ER mainly depends on ER-mitochondrion contact sites [ 345 ]. These contact sites refer to the specific regions where the ER and mitochondria contact each other within the cell, also known as MAM [ 345 ]. Their structures mainly consist of the mitochondrial membrane and the ER membrane, with a distance of approximately 10–30 nm in animal cells [ 346 , 347 ]. This relatively stable region facilitates the exchange of various molecules and signal transduction between them while ensuring the relative independence of the membrane structure of mitochondria and ER [ 344 ]. Besides, multiple proteins are localized on the MAM, such as dynamin-related protein 1 and Parkinson's disease protein 7 [ 346 ]. These proteins assist MAM in intracellular material exchange, Ca 2+ homeostasis, mitochondrial network fusion, ROS signal transduction, and ER stress regulation [ 333 , 348 ]. In addition, the MAM regulates the expression of oncogenes and tumor suppressor genes within the cell as well [ 197 , 349 ].

Calcium homeostasis imbalance

Numerous studies have demonstrated that the disruption of Ca 2+ homeostasis in mitochondria and ER significantly contributes to tumorigenesis [ 349 , 350 ]. Ca 2+ serves as a versatile signaling molecule that regulates several cellular functions, including proliferation, apoptosis, migration, and immunological responses [ 197 ]. It is notable, therefore, that the ER acts as the principal intracellular Ca 2+ reservoir and works in coordination with other organelles to regulate Ca 2+ balance [ 349 ]. Dysregulated Ca 2+ homeostasis is one of the hallmarks of cancer and plays a critical role in tumor initiation and progression [ 197 ]. This process is primarily mediated by the MCU, whose dysregulated expression has been closely linked to the onset and progression of colorectal cancer. The transfer of Ca 2+ from the ER to mitochondria plays a pivotal role in supporting cancer cell survival and proliferation [ 197 ]. Notably, mitochondrial Ca 2+ accumulation can activate Ca 2+ -sensitive dehydrogenases within the tricarboxylic acid cycle, thereby fulfilling the biosynthetic and energy demands of tumor cells [ 197 ]. Moreover, MAMs involving certain protein complexes are required to facilitate the mitochondrial uptake of Ca 2+ , e.g. IP3R and VDACs [ 197 , 351 ]. IP3Rs are overexpressed in various tumors, including hepatocellular carcinoma and breast cancer, promoting cancer cell proliferation and resistance to apoptosis [ 341 ]. Interestingly, VDAC1 promotes ROS generation in lung cancer, whereas VDAC2 protects cells from apoptosis [ 351 ].

Consequently, modulating Ca 2+ homeostasis to simultaneously target mitochondria and ER is an effective strategy for tumor therapy [ 333 ]. For example, an inhalable biomineralized liposome LDM co-loaded with dihydroartemisinin (DHA) and pH-responsive calcium phosphate was developed by Fu et al., as a ferroptosis nano-inducer. This system induced a Ca 2+ -burst-centered ER stress and mitochondrial dysfunction. The initial Ca 2+ surge, triggered by calcium phosphate shell degradation and facilitated by DHA-induced inhibition of SERCA, led to significant ER stress, which in turn disrupted mitochondrial function and increased ROS accumulation, thereby enhancing lung cancer ferroptosis therapy [ 352 ]. In another example, Wang et al. developed ER and mitochondrion dual-targeting nanoparticles (EMT-NPs), capable of synergistically inducing ER stress and mitochondrial dysfunction. These EMT-NPs could efficiently penetrate the ER and mitochondrion at an estimated ratio of 2–3. They could enhance the production of ER stress-related proteins (IRE1α, CHOP), facilitating Ca 2+ efflux and provoking mitochondrial Ca 2+ excess in tumor cells. Additionally, EMT-NPs directly induced oxidative stress within the mitochondria, triggering mitochondrial apoptosis. In summary, the coordinated targeting of mitochondrial and ER signaling networks effectively induces tumor cell death, presenting a promising approach for precision nanomedicine [ 353 ].

Mitochondrial network fusion regulation

The ER and mitochondria engage in continuous interactions, forming a dynamically interconnected network [ 345 ]. Mitochondrial network fusion refers to the dynamic process in which mitochondria fuse their membranes to form an interconnected network within a cell [ 333 ]. Studies have demonstrated that the enhancement and fusion of the mitochondrial network, primarily mediated by MFN-1 and MFN-2 (fusion proteins expressed on the OMM and the ER membrane) are critical for maintaining mitochondrial stability, with MFN-1 playing a dominant role [ 333 ]. This process mitigates ΔΨ m loss, increases OXPHOS, and regulates the release of pro-apoptotic factors, such as Bcl-2 family members and cytochrome C. Consequently, tumor cells gain the ability to resist intrinsic apoptotic signals and enhance their survival capacity [ 354 ]. Furthermore, MFN-2 mediates mitochondrial-ER fusion, facilitating the direct integration of energy supply with the energy demands of protein synthesis, thereby allowing tumor cells to adapt and survive through dynamic changes in protein expression [ 355 ]. To address this mechanism, Milan et al. introduced a novel therapy, cellular organelle mitochondria-ER therapy (COMET), for the treatment of MDR triple-negative breast cancer [ 354 ]. This approach utilized drug-loaded nanoparticles to deliver anti-MFN peptides, disrupting the mitochondrial networks, reducing mitochondrial footprints, altering mitochondrial morphology, and interfering with apoptosis-related processes. Additionally, both drug-loaded nanoparticles and anti-MFN-2 peptides significantly suppressed the activity of mitochondrial complex V, thereby impairing tumor cell OXPHOS. Finally, COMET enabled the targeted delivery of tunicamycin and BAM7 to induce ER stress and trigger mitochondrial apoptosis, respectively. In conclusion, COMET represented a promising therapeutic strategy targeting mitochondrial-ER fusion and functional regulation.

Immune microenvironment regulation

The interaction between MFN-2 and SERCA-2 proteins at mitochondrion-ER membrane contact sites plays a crucial role in supporting the metabolism and function of cytotoxic T lymphocytes while simultaneously promoting MFN-2 expression. This regulatory mechanism modulates the tumor immune microenvironment, ultimately enhancing the efficacy of tumor immunotherapy [ 356 ]. Furthermore, targeting both the ER and mitochondria to exacerbate ER stress and mitochondrial oxidative stress induces ICD in tumor cells [ 221 , 357 ]. During ICD, tumor T cells emit DAMPs, such as calreticulin, high-mobility group box 1, and ATP, which facilitate the maturation of dendritic cells and subsequently activate cytotoxic T lymphocytes to induce tumor eradication, thereby augmenting the effectiveness of tumor immunotherapy [ 358 , 359 ]. For instance, Guo et al. employed cancer CMs to encapsulate polymeric micelles loaded with 1G 3 -Cu and Toy (GCT@CM NPs) ( Fig. 20 ) [ 210 ]. This innovative approach induced pronounced tumor cell apoptosis and ICD by leveraging 1G 3 -Cu-induced oxidative stress and mitochondrial damage—linked to ΔΨ m disruption—alongside Toy-mediated ER stress augmentation. The latter was characterized by the upregulation of ER stress-related factors, including GRP78, XBP1u, and CHOP. Moreover, GCT@CM NPs synergized with anti-programmed death-ligand 1 (anti-PD-L1) therapy to enhance ICD and establish a robust immune memory effect, effectively preventing melanoma recurrence and metastasis. Fig. 20 (a) Schematic representation of the preparation process for GCT@CM nanoparticles. (b) Collaborative tumor suppression was achieved via GCT@CM NP-mediated chemotherapy combined with PD-L1 blockage to enhance the efficacy of tumor immunotherapy [ 210 ]. (Reproduced with permission, copyright 2022, Wiley-VCH.) Fig. 20

Mitochondrion and lysosome targeting strategies

In cells, the mitochondria serve as cellular energy producers, whereas the lysosomes function as recycling stations in cells [ 360 ]. Currently, there is increasing evidence to support the presence of a lysosome-mitochondrion axis [ 361 ]. Their interactions are essential for maintaining intracellular homeostasis. Wang et al. utilized AuNPs to precisely regulate the interactions between lysosomes and mitochondria, enabling the visualization of this process. After being internalized by cells via endocytosis, the AuNPs aggregated in lysosomes in a size-dependent manner, causing lysosomal swelling and increasing the “kiss” events between lysosomes and mitochondria. These enhanced organelle interactions promoted mitochondrial fission. Mitochondria maintain a dynamic network through cycles of fission and fusion, thereby supporting cellular metabolism ( Fig. 21 ) [ 361 ]. Fig. 21 Regulation of mitochondrion-lysosome interaction mitochondria by AuNPs. Unlike molecular reagents, AuNPs enabled controlled, reversible mitochondrial regulation through a sequential process: (1) After endocytosis, AuNPs aggregated in lysosomes in a size-dependent manner, causing lysosomal enlargement and altered motility. (2) Swollen lysosomes increased “kiss” events during “kiss-and-run” interactions with mitochondria. (3) Enhanced organelle interactions promoted mitochondrial fission. (4) Prolonged incubation led to gradual AuNP clearance, restoring mitochondrial fission, metabolic changes, and AuNP levels to baseline [ 361 ]. (Reproduced with permission, copyright 2022, ACS Publication.) Fig. 21

Notably, the interaction between mitochondria and lysosomes is primarily mediated by MCSs [ 362 ]. On the lysosomal membrane, the binding of the Rab7 protein to GTP promotes the establishment and anchoring of mitochondrion-lysosome contact sites [ 339 ]. Meanwhile, the mitochondrial protein TBC1D15 (a Rab7-GAP, GTPase-activating protein for Rab7) recruits the Fis1 protein, which induces Rab7 GTP hydrolysis at the contact site, resulting in the detachment of the MCS [ 360 , 363 ]. These dynamic MCSs facilitate the intracellular transport of lipids, Ca 2+ , and iron ions [ 362 , 364 ]. For instance, the lysosomal cation channel TRPML1 modulates mitochondrial function by releasing Ca 2+ into the mitochondria through MCSs [ 362 , 364 ].

Mitochondrion and lysosome targeting agents

In recent years, research has concentrated on developing nanodrugs with tailored structures to enable dual targeting of lysosomes and mitochondria, thereby enhancing the eradication of tumor cells [ 365 ]. For example, Liang et al. developed an esterase-activated nano-prodrug (DM nano-prodrug), conjugated with a diiodine-substituted fluorogenic malachite green derivative (MG-2I) and the phototherapeutic agent DPP-OH through a hydrolyzable ester linkage ( Fig. 22 a–c) [ 365 ]. Overexpression of esterase in CT-26 mito-FAP cells led to the release of MG-2I and DPP-OH from the DM nano-prodrug, allowing targeted delivery to mitochondria and lysosomes, respectively. Consequently, the NIR-excited DM nanoparticles were able to simultaneously damage both organelles, inducing mitochondrial dysfunction and apoptotic cell death. Fig. 22 Design strategies for nanodrugs targeting the mitochondria and lysosomes. (a) Diagram illustrating the structure of the Mito-FAP plasmid and the ROS generation triggered by MG-2I-COOH/Mito-FAPdL5. (b) Synthesis pathway of DM NPs with pH-responsive dual organelle-targeting. (c) Esterase-activated, pH-responsive, and Mito-FAP-targeted mechanisms driving PDT/PTT-induced cancer cell destruction [ 365 ]. (Reproduced with permission, copyright 2023, Wiley-VCH.) (d) DM-CaCO 3 @L-PEG NPs mediated tumor therapy by inducing apoptosis and paraptosis pathways. (e–f) Structural diagram of CaCO 3 @L-PEG nanoparticles. (g) Ultrathin sections of 4T1 cells treated with DM-CaCO 3 @L-PEG nanoparticles were examined morphologically. (h–i) Confocal scanning microscopy images of 4T1 cells treated with DM-CaCO 3 @L-PEG nanoparticles [ 368 ]. (Reproduced with permission, copyright 2024, ACS Publication.) Fig. 22

Lysosome-mitochondrion axis modulation

In addition to the design of mitochondrion and lysosome targeting agents, recent investigations have shown that activation of the lysosome-mitochondrion pathway through modulation of the lysosome-mitochondrion axis mediates a cascade of reactions that enhance the killing of tumor cells [ 366 , 367 ]. For example, Lin et al. devised a biological DDS by conjugating human red blood cell (RBC)-derived vesicles (RDVs) conjugated with DOX using glutaraldehyde (Glu) (DOX-GluRDVs). The DOX-GluRDVs were able to effectively deliver and accumulate DOX in the lysosomes of the drug-resistant cells. This process facilitated the transfer of Ca 2+ from lysosomes to adjacent mitochondria, leading to excessive mitochondrial ROS production, loss of membrane potential, and activation of apoptotic signaling pathways. These vesicles significantly inhibited MDR in uterine sarcoma MES-SA/Dx5 cells [ 366 ]. Similarly, Qian et al. developed tumor-targeting nanoparticles ( 131 I-EM@ALA) by encapsulating 5-aminolevulinic acid into a 131 I-labeled exosome mimetic structure for the treatment of breast cancer. These nanoparticles effectively activated lysosome-mitochondrion-axis-dependent cell death pathways and induced tumor-killing effects [ 367 ].

Calcium homeostasis imbalance

Recent studies have demonstrated that lysosomal degradation promotes Ca 2+ release, which can induce mitochondrial calcium overload and oxidative stress, leading to mitochondrial dysfunction and tumor cell death [ 368 , 369 ]. Guo et al. developed a Ca 2+ /Cu 2+ dual-ion “nano-trap” that effectively induced both paraptosis and apoptosis by targeting the lysosomes and mitochondria for breast cancer therapy. The synthesized nano-traps were found to undergo acid-induced biodegradation within the lysosomes, thus releasing Ca 2+ , Cu 2+ , and disulfiram (DSF). The released Ca 2+ subsequently induced mitochondrial calcium overload, resulting in excessive ROS production. Concurrently, Ca 2+ /ROS-induced mitochondrial dysfunction triggered paraptosis in the tumor cells ( Fig. 22 d–i) [ 368 ]. Using a different approach, Huang et al. designed an ion homeostasis perturbator (CTC) by co-encapsulating carvacrol (CAR) and meso-tetra-(4-carboxyphenyl) porphine (TCPP) in pH-sensitive nano-CaCO 3 . The lysosomal acidity decomposed the CaCO 3 , leading to rapid Ca 2+ overload and CO 2 formation in the cytoplasm, which further enhanced the production of ROS. This oxidative stress-augmented Ca 2+ /Mg 2+ interference therapy effectively disrupted the function of the tumor mitochondria, ultimately causing the death of the tumor cells [ 369 ].

Endoplasmic reticulum and Golgi apparatus targeting strategies

The ER-Golgi system is composed of the ER, GA and ER-Golgi intermediate compartment (ERGIC), a membranous structure that is present in mammalian cells [ 333 , 370 ]. The ERGIC is specifically located between ER and GA, playing a crucial role in transporting proteins from ER to GA. The primary function of the ER-Golgi system is to regulate protein synthesis, transport, and secretion [ 333 ]. The ER-Golgi contact sites are vital for protein transport within the system, mediated by vesicles coated with COPII and COPI [ 194 , 371 ]. The contact sites also contribute to lipid synthesis and the biosynthesis of several organelles, including autophagosomes and peroxisomes [ 372 ]. In addition, this system is essential for secretory trafficking, where proteins are translocated into the ER lumen via the SRP-SEC61 complex, accumulate at the ER export sites (ERESs), and are subsequently transported to the ERGIC or GA via the COPII coating process [ 333 ]. Notably, the ER-Golgi contact sites are dynamic and closely linked to the physiological state of the cell [ 194 ]. Under stress conditions, for instance, the interaction between the ERGIC and ERESs can lead to reorganization and formation of new membrane connections that are critical for the formation of early autophagosome precursors [ 373 , 374 ]. In summary, the ER-Golgi system is dynamic and versatile. It facilitates intracellular signaling and material transport via vesicular trafficking and membrane interactions to maintain homeostasis within the cell [ 194 , 334 ].

Endoplasmic reticulum and Golgi apparatus targeting agents

Currently, the obliteration of the ER-Golgi system inside the tumors has proven to be an efficient strategy for inhibiting tumor proliferation and metastasis [ 232 , 375 ]. In recent years, research has increasingly focused on developing nanodrugs with precisely engineered structures to achieve dual targeting of the ER and GA, thereby enhancing tumor cell eradication. For instance, Liu et al. reported the GSH-responsive, in situ self-sorting peptide assemblies within tumor cells [ 375 ]. They designed and synthesized two peptides, E3C16E6 and EVMSe, which exhibited strong affinities for the GA and ER, respectively, enabling intracellular self-sorting and organelle-specific targeting. These peptides effectively disrupted the functions of both organelles, ultimately inducing tumor cell death and offering a novel strategy for drug delivery and intracellular process regulation.

Protein synthesis and transport disruption

The ER-Golgi system plays a crucial role in regulating protein synthesis, transport, and secretion. Targeting this system can disrupt tumor-associated protein synthesis, thereby enhancing antitumor efficacy. One notable example is PD-L1, a key immune checkpoint protein that facilitates tumor immune evasion [ 376 ]. As a membrane protein, its synthesis and transport are tightly linked to the ER and GA. To leverage this, Ye et al. developed a GA-Pd-L1 −/− exosome hybrid membrane coated nanoparticles (GENPs) designed to interfere with the endosome-Golgi-ER transport pathway, thereby obstructing the synthesis and secretion of PD-L1 [ 232 ]. By incorporating GA membrane components, these GENPs facilitated the targeted delivery of RA to the GA via the endosome-Golgi-ER pathway, ultimately disrupting GA structural integrity and initiating a cascade of cellular responses. First, as the GA was essential for protein transport and modification, its disruption impaired PD-L1 glycosylation, thereby suppressing its expression on the cell surface. Additionally, GA damage induced the retrograde transport of PD-L1 into the cytoplasm, where it underwent ER-associated degradation via the proteasomes. Moreover, GA dysfunction inhibited exosome release, reducing PD-L1-enriched exosome production, which helped mitigate melanoma-associated immune suppression. Beyond these direct effects, the cascade reaction triggered by GA disruption further destabilized ER homeostasis, leading to ER stress and subsequently activating a systemic immune response. This strategy demonstrated significant efficacy in metastatic melanoma treatment, effectively reducing tumor recurrence and prolonging survival.

Lysosome degradation pathway evasion

Targeting the ER-Golgi system has emerged as a promising and safe drug delivery strategy, enabling therapeutics to reach specific subcellular targets via the endosome-Golgi-ER pathway while circumventing degradation through the endosome-lysosome pathway [ 375 ]. This approach effectively enhances therapeutic efficacy by preserving drug stability and prolonging intracellular retention.

For instance, Qiu et al. extracted ER membranes from cancer cells to fabricate integrative hybrid nanoplexes (EhCv/siRNA NPs) aimed at enhancing the transfection efficiency of siRNA ( Fig. 23 a–c) [ 377 ]. These ER membrane-modified EhCv/siRNA NPs entered cells via caveolae-mediated endocytosis and efficiently transported siRNA through the endosome-Golgi-ER pathway. The Golgi-associated COPI vesicles further facilitated the retrograde transport of siRNA from GA to ER, enhancing its retention within the ER and preventing lysosomal degradation. This strategy significantly improved gene silencing efficiency and ultimately enhanced tumor therapeutic outcomes. Similarly, Wang et al. conjugated the KDEL peptide to CS to create KDEL-grafted CS (CK) and developed CPD/siRNA/CK nanocomplexes ( Fig. 23 d and e) [ 378 ]. On the one hand, CS targeted the CD44 receptor, facilitating transport through GA; on the other hand, the conjugated KDEL peptide guided the nanocomplexes in retrograde transport from the GA to ER, thereby reducing “random” Golgi/ER-related exocytosis. Fig. 23 Schematic illustration of ER-Golgi system-targeting nanodrugs downregulating lysosomal degradation pathways for precise tumor therapy. (a) Schematic representation of the intracellular trafficking pathways of different NPs. (b) Diagram illustrating the inhibitory effect of Golgicide A. (c) Representative images showing the colocalization of EhCv/siRNA NPs with the ER, GA, and lysosome, with or without Golgicide A treatment [ 377 ]. (Reproduced with permission, copyright 2019, Nature Portfolio.) (d) CPD/siRNA/CS was internalized via caveolin- and thiol-mediated uptake, bypassing endolysosomal degradation and targeting GA. GSH-responsive depolymerization released siRNA, although ER/GA-associated exocytosis remained unresolved. (e) Monensin enhanced RNAi by inhibiting exocytosis and autophagy, while KDEL modification directed sorting to the ER, reducing exocytosis [ 378 ]. (Reproduced with permission, copyright 2025, ACS Publication.) Fig. 23

In summary, the ER-Golgi system targeting strategy can effectively prevent lysosomal degradation of nanodrugs. However, challenges remain, such as insufficient siRNA release and the risk of exocytosis [ 379 ]. Therefore, enhancing retrograde transport and optimizing directed sorting from the GA to ER will be more effective in minimizing exocytosis, improving nanodrug retention in the ER, and ultimately boosting the therapeutic efficacy against tumors [ 380 ].

Mitochondrion and nucleus targeting strategies

The dynamic interplay between mitochondria and nucleus is crucial for regulating gene expression and facilitating the transmission of signaling molecules [ 381 , 382 ]. The signaling molecules involved in this crosstalk include Ca 2+ , NAD + /NADH, AMP-activated protein kinase signaling, and redox-associated molecules, such as ROS, RNS, and APE1, etc . [ 383 , 384 ]. These signal molecule exchanges influence energy generation, metabolic regulation, and the cellular response to environmental fluctuations [ 328 , 382 ].

Notably, mitochondrion-nucleus communication is bidirectional: anterograde signals pass from the nucleus to the mitochondria, while retrograde signals pass from the mitochondria to the nucleus [ 384 ]. Anterograde signaling by the nucleus is used to regulate mitochondrial biogenesis and function (e.g. proteins encoded by nuclear genes are synthesized and imported into the mitochondria to facilitate the assembly of mitochondrial enzyme complexes) [ 385 ]. Retrograde signaling, on the other hand, occurs when the mitochondria report changes in their functional status to the nucleus via specific signaling molecules, which in turn modulate nuclear gene expression. This process plays a crucial role in cellular adaptation [ 386 ]. In summary, the complex and intricate crosstalk that occurs between the nucleus and mitochondria is a key component of cellular physiology and homeostasis.

It is thought that disruptions to the communications between the nucleus and mitochondria may have a role to play in cancer development [ 349 ]. For example, mitochondria generate ROS as they carry out their energy-releasing reactions and it is well known that these species can damage DNA (both nDNA and mtDNA), resulting in genetic mutation [ 349 , 383 ]. Additionally, mitochondria are involved in the regulation of apoptosis, including cell death signaling, the release of cytochrome C, and the activation of caspase-3 in the nucleus, as well as cell cycle regulation through tumor suppressor proteins such as p53 [ 142 , 349 ]. Mitochondrial failure can result in aberrant expression of associated signaling molecules in the nucleus, ultimately leading to tumor cell proliferation and the onset of cancer [ 383 ]. Currently, researchers have developed a variety of nanodrug delivery systems designed to specifically target mitochondria and nucleus within tumor cells, enabling highly effective tumor destruction [ 387 , 388 ]. For example, Cui et al. applied a bioorthogonal copper-free click chemistry strategy to construct nanoparticles utilizing aggregation-induced emission photosensitizer (BODTPE) for tumor-targeted therapy ( Fig. 24 ) [ 387 ]. Their formulation resulted in the selective accumulation of NP-DBD at tumor sites. The combined PDT and PTT effects boosted by NIR-II damaged both the mtDNA and nDNA as well as enhanced the activation of the cGAS-STING pathway in the tumor cells, promoting dendritic cell maturation and INF-β secretion. This resulted in a pronounced tumor inhibition effect augmented by robust immune modulation. Similarly, Zhang et al. employed CBNs to devise a novel nanodrug delivery system (CPD). This system enhanced the accumulation of DOX in tumor cells and achieved a targeting rate of 36.8 % in the nucleus. The CPD modulated the expression of caspase-3, p53, and Bcl-2 genes by elevating intracellular ROS levels and reducing the ΔΨ m (thus signifying the occurrence of mitochondrion-mediated apoptosis). As a result, tumor growth was suppressed by 79.4 ± 2.8 %, while therapeutic side effects were significantly reduced [ 142 ]. In conclusion, concurrently co-targeting mitochondria and the nucleus offers a promising antitumor therapeutic strategy [ 387 , 388 ]. Fig. 24 Schematic representation of the synthesis process for the polymer DBD and the formation of NP-DBD nanoparticles. (a) Stepwise synthesis process of the DBD polymer. (b) Chemical structure of BODTPE. (c) Formation of NP-DBD through the nanoprecipitation method. (d) NP-DBD nanoparticles anchored to the CMs pretreated with Ac4ManNAz via a bioorthogonal copper-free click reaction. This enhanced the combined effects of PDT and PTT, boosted by NIR-II FLI, while simultaneously activating the cGAS-STING pathway, leading to dendritic cell maturation and robust antitumor immune responses [ 387 ]. (Reproduced with permission, copyright 2023, Wiley-VCH.) Fig. 24

However, it is worth noting that current research on co-targeting mitochondria and the nucleus in nanomedicine is still focused on targeting each organelle separately. Future studies should explore how to interfere with the interactions and communications between mitochondria and nucleus, disrupting the adaptive mechanisms of tumor cells, in order to achieve a therapeutic effect where 1 + 1 > 2.

Triple organelle targeting strategies

As mentioned above, cellular homeostasis involves balancing the various physiological processes necessary to sustain life. This is achieved by coordinating the interactions among various organelles, primarily the mitochondria, nucleus, lysosomes, ER, GA and so on [ 197 , 389 ]. Every organelle plays a distinct but interconnected role in preserving cellular function, responding to stressors, and regulating cell fate [ 313 , 390 ]. For example, the nucleus regulates gene expression in response to stress signals [ 391 ], mitochondria provide energy and regulate apoptosis signaling [ 392 ], and the ER ensures proper protein folding and Ca 2+ homeostasis [ 197 ]. Together, these organelles form a complex communication network in the intracellular microenvironment. In brief, multiple organelle interaction is complicated but vital for cellular homeostasis. The dysfunction of organelle interaction can contribute to tumor development, highlighting the importance of incorporating multi-organelle coordination into the design of nanomedicines as an ideal strategy for precise tumor therapy.

Calcium homeostasis regulation

Ca 2+ plays a critical role in various biological processes within organelles. In mitochondria, they regulate key enzymatic activities involved in energy metabolism, stabilize the ΔΨ m , and support ATP production. The ER relies on tightly controlled Ca 2+ concentrations to facilitate protein folding, post-translational modifications, and calcium storage. A well-regulated Ca 2+ environment ensures proper protein folding and maintains ER homeostasis. Similarly, the GA depends on Ca 2+ for protein transport and processing, ensuring efficient intracellular trafficking and secretion [ 393 ].

Disruptions in Ca 2+ transmission or homeostasis—whether induced by chemical agents such as ethylenebis (oxyethylenenitrilo) tetraacetic acid (EGTA, which chelates Ca 2+ ) or other factors interfering with calcium flux between organelles—can severely impair cellular function. Mitochondrial dysfunction leads to impaired ATP production, compromising the energy supply essential for tumor cell survival. In the ER, calcium imbalance can result in the accumulation of misfolded proteins, triggering stress responses and potentially activating apoptotic signaling pathways. Additionally, disturbances in the GA disrupt protein transport and secretion, interfering with the processing and trafficking of proteins necessary for tumor growth and metastasis. Collectively, these disruptions impair tumor cell survival, proliferation, and metastatic potential on multiple levels [ 393 ].

To counteract this, Chang et al. fabricated an intelligent nanoplatform (BMA EF ) to target the GA, ER, and mitochondria of tumor cells by exploiting the over-expression of Ca 2+ to activate photothermal immunotherapy ( Fig. 25 a and b) [ 394 ]. The BMA EF was loaded with brefeldin A conjugated to EGTA and AuNPs co-modified with FA (A EF ). When released, the EGTA captured Ca 2+ and thus blocked ion transfer between the GA, ER, and mitochondria, thus inducing the dysfunction of all three organelles. The nanoplatform also caused the aggregation of A EF in the tumor cells, which consequently led to enhanced breast tumor-specific photothermal-assisted immunotherapy [ 116 ]. By disrupting energy metabolism, biosynthesis, and immune activation pathways, this multi-organelle synergistic targeting strategy effectively suppressed tumor growth and metastasis. This innovative approach presented a promising avenue for breast cancer treatment and held significant potential for further development and clinical translation in future tumor therapies. Fig. 25 Triple organelle targeting strategies for precise tumor therapy. Schematic representation of BMA EF nanoparticle preparation (a) and therapeutic mechanism (b), which enabled tumor-specific photothermal-immunotherapy. This strategy involved lysosome-mediated controlled release and targeted disruption of Mito/GA, suppressing tumor cell energy and material metabolism through specific Ca 2+ signaling regulation and intracellular release of Bre (an inhibitor of Mito/GA) [ 394 ]. (Reproduced with permission, copyright 2024, Wiley-VCH.) (c) Schematic diagram of COMBO synthesis. (d) COMBO accumulated in tumor cells via endocytosis. GSH depletion released DOX and morusin, inducing ER stress, mitochondrial/ER vacuolation, and paraptosis via CHOP, IRE1α, and p-eIF2α upregulation. Meanwhile, DOX caused nuclear damage, enhancing the effects of the combined therapy [ 399 ]. (Reproduced with permission, copyright 2021, Elsevier B.V.) Fig. 25

Apoptosis regulation

The interactions between the nucleus, ER, and mitochondria are essential for Ca 2+ signaling and the regulation of cellular response to DNA damage. When DNA damage is detected, the nucleus activates ATM and ATR kinases, thus stabilizing the tumor suppressor protein p53 [ 395 ]. Beyond inducing cell cycle arrest and apoptosis, p53 initiates signals that influence both the ER and mitochondria. The ER, as a major Ca 2+ reservoir, releases Ca 2+ into the cytoplasm under stress, which is then taken up by the mitochondria. This process triggers OMM permeabilization, leading to cytochrome C release and activation of the intrinsic apoptotic pathway [ 396 , 397 ]. Concurrently, the nucleus enhances the expression of pro-apoptotic genes, such as Bax, which reinforces the OMM permeabilization process and strengthens apoptosis signaling [ 398 ].

Based on the interactions among the nucleus, ER, and mitochondria, Zheng et al. developed a Cu 2+ -coordinated morusin/DOX biological organizer (designated as COMBO) to target the nucleus, ER, and mitochondria through a combination of paraptosis and apoptosis ( Fig. 25 c and d) [ 399 ]. On the one hand, the DOX component became preferentially located in the nucleus of the tumor cells. On the other hand, the morusin component of COMBO mediated paraptosis which induced extensive vacuolization via ER and mitochondrion dilation, thus leading to non-apoptotic PCD. This ultimately resulted in cell apoptosis, thus producing a combination of chemotherapeutic effects. The overall therapeutic outcome was therefore enhanced, demonstrating the advantages of multi-organelle collaborative targeting therapy for tumor inhibition rather than a single organelle targeting approach.

Autophagy regulation

Notably, mitochondria, ER, and lysosomes interact to regulate autophagy, a crucial process for cellular metabolism and energy balance. Autophagy degrades damaged organelles and maintains energy homeostasis, especially when the cell is subject to nutrient deprivation or metabolic stress [ 161 ]. Mitochondrial damage can lead to the transfer of Ca 2+ from ER to mitochondria, resulting in the excessive production of ROS, activation of the AMP-activated protein kinase pathway, and subsequent initiation of ER-mediated mitophagy to eliminate damaged mitochondria [ 400 , 401 ]. Lysosomes, the final site of autophagic degradation, break down dysfunctional mitochondria using their hydrolases [ 402 ]. Disruption of the mitochondrion-ER-lysosome axis contributes to various diseases, such as cancer [ 403 ]. Therefore, targeting these pathways with nanodrugs as part of tumor therapy may enhance autophagy and help restore cellular homeostasis, improving therapeutic outcomes. For example, in order to address chemotherapy resistance in pancreatic cancer and improve patient prognosis, Zhao et al. designed a drug delivery nanocage GEM-DVDMS@MOFs@COF-NRP2 (GDMCN2), which increased the sensitivity of pancreatic cancer cells and exerted therapeutic effect by targeting mitochondrion, ER and lysosome. This was achieved through the induction of autophagy and metabolic imbalance. When irradiated with ultrasound, the GDMCN2 nanocages generated copious amounts of ROS, which activated the mitochondrial transition pores, leading to Ca 2+ release, ER stress, and, ultimately, lysosomal autophagy. Besides, the process also triggered autophagy-dependent ferroptosis, further increasing the sensitivity of pancreatic cancer cells to chemotherapeutic drugs. In summary, this approach demonstrated the potential to eradicate pancreatic cancer [ 404 ].

In conclusion, multi-organelle targeting strategies account for the intricate interaction and communication among different organelles, providing a more comprehensive impact on the intracellular microenvironment. Compared to single-organelle targeting approaches, multiple-organelle targeting strategies typically achieve significantly enhanced tumor cell eradication. As our understanding of organelle functions and their interplay deepens, innovative therapeutic strategies aimed at disrupting homeostasis in cancer cells are likely to emerge. This progress is expected to drive the development of novel tumor therapies, ultimately improving patient prognosis.

Brief summary and prospect

Similar to nanodrugs designed with the consideration of escaping specific organelles, the therapeutic efficiency of nanodrugs is significantly enhanced when they target multiple organelles simultaneously. It is worth noting that in most current designs of multi-organelle targeting nanodrugs, the selection of targeted organelles does not fully consider the physiological interactions among different organelles. As a result, the therapeutic effect of the nanodrugs increases only linearly (i.e., 1 + 1 = 2). In contrast, when targeted organelles are selected based on the synergistic relationships among their functions (as exemplified by the work of Zhang et al.), the corresponding therapeutic effect of the nanodrug increases substantially (i.e., 1 + 1 > 2) [ 404 ]. Although material scientists may face various challenges when designing nanodrugs based on organelle interaction and crosstalk (e.g., integrating targeting functions for multiple organelles into the nanostructures, as well as addressing interactions between specific targeting structures), such efforts are worthwhile as they can yield greater practical benefits. Furthermore, a series of recent molecular biology studies have comprehensively elucidated organelle interactions, providing material scientists with a more systematic design framework.

On the other hand, designing nanodrugs that target two organelles simultaneously has shown considerable improvements in therapeutic efficiency. However, as more target organelles are added (three or more), the challenges associated with material design and preparation increase. In fact, balancing the increased difficulty of preparation with the enhancement in therapeutic efficiency is crucial in the design of multi-organelle targeting nanodrugs, a concept known as the marginal returns issue. However, the marginal relationship between the number of target organelles, the complexity of nanostructure design, and therapeutic efficiency has not yet been fully addressed.

Conclusions and perspectives

Since the advent of precise tumor therapy, organelle-targeting nanomedicines have made significant strides in tumor treatment over the past decade [ 6 , 7 ]. Their remarkable progress is attributable to their high specificity, efficient targeting capabilities, multifunctional therapeutic platform, and minimal side effects. Several previous reviews have comprehensively summarized the advancements in the field of organelle-targeting nanomedicine, offering systematic and insightful references for further research [ 405 , 406 ]. For instance, Wang et al. provided an overview of the endocytosis pathways of nanodrugs and subsequent organelle-targeting strategies, particularly focusing on the diverse endocytic pathways and proposing innovative ideas for the design of tumor-targeting nanodrugs [ 407 ]. Building on these foundational works, we present a systematic review of organelle-targeting strategies from a biological perspective, focusing on organelle structure and function. This review highlights precise tumor therapy strategies targeting various organelles, including mitochondria, nucleus, lysosomes, ER, GA, and proteasomes. The review furthers our understanding of the biological characteristics (e.g., structural and functional features) and physicochemical properties (e.g., surface charge and molecular characteristics) of different organelles. This, in turn, should help to improve the rational design of nanodrugs required for organelle targeting (by optimizing their size, charge, and surface properties).

Furthermore, this review adopts a more comprehensive and holistic perspective given that organelles are not isolated entities (but are, as we have seen, interconnected and interacting closely with one another). It examines the processes by which nanodrugs enter cells and are transported among different organelles, taking into account both the targeting and escaping properties of the nanodrugs employed. This design approach enhances the targeting efficiency of the nanodrugs whilst minimizing the risk of degradation by non-targeted organelles (e.g. lysosomes and proteasomes) before they reach their intended target. This strategy facilitates the precise localization, internalization, and efficient accumulation of nanodrugs within tumor cells. Notably, this review also investigates the interaction, communication, and collaboration that occur among multiple organelles, thus emphasizing that the development of multi-organelle collaborative targeting strategies is crucial for improving the efficacy of organelle-targeting therapy.

In summary, this review is based on a robust biological framework that elucidates the functions of various organelles and their interactions from a more comprehensive perspective. At the same time, it also explains advanced biological mechanisms and insights that have yet to fully guide the design of nanomedicines. Furthermore, this review revisits previous studies and reorganizes/reclassifies them whilst integrating the latest developments in nanomedicine research. This work aims to assist scientists in designing more effective organelle-targeting nanomedicines by providing valuable biological insights, thus further advancing the further development of precise tumor therapy ( Fig. 26 ). Fig. 26 (a) The number of research articles related to nanodrugs targeting different organelles (mitochondria, nuclei, lysosomes, ER, GA, and proteasomes) since 2003, search results obtained from PubMed. (b) Proportions of research articles focused on targeting individual organelles, organelle escape, and multi-organelle collaborative targeting. (Created with BioRender.com.) Fig. 26

However, the ultimate goal-achieving precise treatments for all known types of tumors-remains a long-term challenge. Moreover, the core issues limiting the application of organelle-targeting nanomedicines in precise tumor therapy are not unique; rather, they are common obstacles encountered in the broader use of nanomaterials in biological contexts. From our perspective, five key points warrant further consideration:

The interactions among different organelles cannot be overlooked in the design of organelle-targeting nanomedicines. As emphasized at the beginning of this review, the interactions among different organelles in tumor cells stand out as a pivotal consideration when designing organelle-targeting nanomedicines. This aspect becomes particularly important when the structures of the nanomedicines are refined, as it can enhance the organelle targeting effect and bolster the efficacy of precision therapy. Both targeting and escape are equally significant when designing nanomaterials. For instance, most organelle-targeting nanomedicines must have the ability to escape lysosome to their intended targets. Additionally, interactions and communications between various organelles are essential for maintaining cellular homeostasis. Disrupting this homeostasis can induce cell death, thereby promoting the tumor-killing effect. Furthermore, nanomedicines capable of targeting multiple organelles have been shown to achieve superior therapeutic outcomes compared to those targeting only one organelle. For optimal therapeutic efficacy, careful selection of organelles for joint targeting is essential. To summarize, the cornerstone strategy for improving the efficacy of nanomedicines lies in designing their structures based on a comprehensive understanding of organelle interactions.

A more rational classification system for tumors holds the promise of providing fresh insight into precise tumor therapy. Recent comments made by André et al. in Nature suggested there was a growing disparity in precise oncology applications due to the convention that cancers were classified by their organ of origin (thus, we spoke of lung, breast, and prostate cancer, etc .) [ 408 ]. In contrast, precision oncology should determine treatment strategies based on the molecular profiles of tumor cells and immune cells involved [ 409 ]. For instance, Saliby et al. identified seven molecular subtypes that influenced the treatment of renal cell carcinoma by analyzing the molecular characteristics of 823 tumors, and then evaluated their effectiveness in predicting the responses to various immunotherapies [ 410 ]. This suggests that adopting a more rational classification system could help drive further advances in precise tumor therapy in the future. With the guidance of such a classification system, researchers can gain valuable insight into the tumors of concern which would help them develop innovative nanomedicines tailored to the molecular characteristics of the tumor itself rather than its location.

A more profound integration of material science and biology is required to further the advancement of nanomedicines. The development of nanomedicines is inherently interdisciplinary, demanding expertise in both material science and biology. Researchers therefore need to possess a robust understanding of both disciplines [ 411 , 412 ]. However, the current level of integration between these fields remains superficial, preventing the full potential of their respective strengths from being realized. For example, organelle-targeting nanodrugs are typically designed to target organelles through specific molecular modifications which relegate the nanomaterials to mere carriers for the core drugs. This approach overlooks the unique properties of the nanomaterials in a biological context. For instance, in metastatic tumor therapies that used graphene oxide, the graphene-based nanomaterial not only served as a drug carrier for tumor treatment but also interacted directly with the cytoskeleton itself. This meant the graphene-based nanomaterial could also be used to regulate cancer stem cell differentiation in order to achieve a better therapeutic effect [ 413 ]. Therefore, a more thorough integration of material science and biology is crucial to elucidating and harnessing the biological functions of nanomaterials. Clarifying the relationships between the structures of different nanomaterial interfaces and their biological activities will not only drive the development of novel biological applications but also provide valuable insights into the structural design of other therapeutic agents.

The application of machine learning to nanomedicine design will significantly promote further exploration. In the era of precision medicine, artificial intelligence (AI) can be expected to play a pivotal role in tumor diagnosis and treatment recommendation, further driving the demand for precision medicines [ 414 , 415 ]. Potential applications of AI include early tumor screening, molecular characterization, patient prognosis, treatment response prediction, personalized treatment drugs development adapted to individuals, and optimization of clinical trials [ 416 ]. Notably, machine learning offers convenience in analyzing variable relationships within multivariate systems. However, for biological mechanisms grounded in atomic physical processes, machine learning falls short of meeting the mathematical elegance pursued by physics. When designing antitumor nanomedicines, numerous variables need to be simultaneously considered, including the structural properties of the nanomaterials and treatment-related factors. The complexity of these data presents challenges in analyzing therapeutic mechanisms and formulating effective treatment plans. Recent advancements in machine learning have demonstrated its value in managing big data systems, which generally involve vast, complex datasets with numerous variables [ 417 ]. It is noteworthy that Ren et al. recently developed a novel drug for lung disease treatment using AI for the first time [ 418 ]. However, progress in this field is currently limited by two major challenges: computational power and sample size. Addressing the “black box” nature of machine learning and translating mathematical models into scientifically meaningful mechanisms are essential for further progress. Balancing the issue of data security with the need for collaborative research is crucial for overcoming obstacles in the development of machine learning methodologies.

The market-oriented development of nanomedicines still has a long way to go, facing several significant challenges. Firstly, nanomedicine research is still in its nascent stages, with most studies confined to small-scale laboratory experiments. The therapeutic efficacy observed in these studies is often difficult to reproduce in clinical trials, significantly limiting the translational potential and practical application of these findings [ 419 ]. Secondly, the long-term and systematic evaluation of nanomedicine safety in humans is inadequate, posing significant risks in clinical applications [ 420 ]. Regarding biodistribution, nanomedicines may persist in systemic circulation for extended periods, with their distribution being only partially controllable, which can lead to unintended damage to off-target tissues. In terms of metabolism, while many nanomedicines are eliminated via the renal system or mononuclear phagocyte system, certain metallic and non-biodegradable nanomaterials may accumulate in the body, increasing the risk of chronic toxicity. Furthermore, high-blood-flow organs such as the liver, spleen, lung, and kidney are particularly susceptible to nanoparticles, making them more prone to inflammation, fibrosis, and metabolic dysregulation, ultimately causing nonspecific damage to normal tissues. To address these issues, the design of nanomedicines must be guided by systematic evaluations that incorporate in vivo and in vitro studies, computational modeling, and ecotoxicological assessments, ensuring the long-term safety and efficacy of nanomedicines for clinical use.

Simultaneously, the issue of nanomaterial-induced environmental pollution remains unresolved [ 421 ]. During the production, utilization, and disposal of nanomedicines, nanoparticles may be inadvertently released into the environment, where they can accumulate. Their unique properties, such as the persistence and bioaccumulation of metallic or carbon-based nanoparticles, pose significant risks to ecological stability through potential cumulative effects on ecosystems. Additionally, emissions and wastewater containing nanoparticles may arise during production processes, and the current lack of effective treatment technologies for nano-waste exacerbates the risk of widespread environmental contamination.

To mitigate these risks, stringent, systematic, and standardized regulatory frameworks are essential for ensuring the efficacy, safety, and sustainability of nanomedicine applications. For instance, rigorous quality control measures should encompass the selection of raw materials, manufacturing processes, and final product quality. Comprehensive toxicological assessments and adverse reaction evaluations are imperative at both preclinical and clinical trial stages. Additionally, environmental risk assessments should ensure compliance with ecological protection guidelines, requiring companies to provide environmental exposure data and evaluate associated risks [ 419 ].

In conclusion, the disparity between laboratory research and industrial-scale development significantly impedes the commercialization of nanomedicines [ 422 ]. Basic research must become more oriented toward clinical challenges and market demands, supported by adequate funding. Prioritizing precision therapies for malignancies with urgent clinical needs will enhance the translational relevance of laboratory research, facilitate the implementation of clinical trials, and address critical aspects such as safety, efficacy, dose optimization, and potential long-term side effects. These efforts will ultimately strengthen investor confidence and promote the advancement of nanomedicine toward practical and commercial applications.

CRediT authorship contribution statement

Kexin Tan: Writing – original draft, Visualization, Software, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Haiyang Zhang: Writing – review & editing, Validation, Methodology, Formal analysis, Data curation, Conceptualization. Jianyuan Yang: Writing – original draft, Visualization, Software, Methodology, Investigation, Formal analysis, Data curation. Hang Wang: Writing – original draft, Visualization, Validation, Software, Resources, Data curation, Conceptualization. Yongqiang Li: Validation, Supervision, Methodology. Guqiao Ding: Writing – review & editing, Validation, Supervision, Project administration, Funding acquisition. Ping Gu: Validation, Supervision, Project administration. Siwei Yang: Writing – review & editing, Visualization, Validation, Supervision, Project administration, Methodology, Funding acquisition, Conceptualization. Jipeng Li: Writing – review & editing, Validation, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Conceptualization. Xianqun Fan: Writing – review & editing, Validation, Supervision, Resources, Project administration, Investigation, Funding acquisition, Conceptualization.

Ethics approval and consent to participate

This review article does not require any ethical approval or allied consent for publication.

Declaration of AI-assisted technologies in the writing process

During the preparation of this manuscript, the authors utilized ChatGPT to assist in polishing the content. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the final content of the publication.

Declaration of competing interest

The authors declare no conflict of interest.

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Kexin Tan obtained her bachelor's degree from the Shanghai Jiao Tong University School of Medicine in 2023, majoring in Clinical Medicine. She is currently an MD student in the Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. She received National Scholarships for undergraduates in 2021 and 2022. Her research interests include tumor diagnosis and therapy, biomaterials, and tissue engineering.

Haiyang Zhang is an MD candidate at the Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. His research interests are focus on orbital disease and ocular tumors, especially their multimodal imaging and advanced treatment using advanced techniques of the ophthalmic diseases. He has received several National Scholarships (3 times), and also won the Shanghai College Student of the Year (2021), Shanghai Youth Eye Health Promotion Contest Grand Prize (2023).

Jianyuan Yang is currently an undergraduate student at Shanghai Jiao Tong University School of Medicine, majoring in Clinical Medicine. He received a National Scholarship for undergraduates in 2023.

Hang Wang obtained her BSc degree from Ningbo University in 2021, majoring in Microelectronics Science and Engineering. She is currently a PhD student at the Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Science. Her research interests include the synthesis and application of graphene quantum dots to tumor diagnosis and therapy, and biomicroelectronics.

Siwei Yang is a professor at the Shanghai Institute of Microsystem and Information Technology (SIMIT), Chinese Academy of Science. He received his PhD from SIMIT in 2017. Dr Yang first prepared the new 2D carbon-based semiconductor C 3 N in 2017. His research interests include controllable preparation, applications of 2D carbon-based semiconductors (for use in nanoelectronics, nanophotonics, and nanomedicine), and graphene quantum dots and other graphene-based derivatives.

Jipeng Li obtained his PhD from Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, majoring in Ophthalmology. He is currently a resident physician in ophthalmology in Shanghai Ninth People's Hospital. He is engaged in researching the application of biomaterials to the diagnosis and treatment of orbital diseases and has published more than 10 papers in internationally-recognized journals, including Advanced Materials , Advanced Functional Materials , and ACS Applied Materials & Interfaces . He has presided over the National Natural Fund Youth Project, Shanghai Yangfan Plan Talent Project, and Doctoral Innovation Fund of the Shanghai Jiao Tong University School of Medicine.

Xianqun Fan , academician of the Chinese Academy of Engineering, is an ophthalmologist, the Ministry of Education of Yangtze River Scholar Professor, and a deputy to the 14th National People's Congress of China. He is currently the Vice President of Shanghai Jiao Tong University, Chancellor of Shanghai Jiao Tong University School of Medicine, and Director of the Shanghai Key Laboratory of Orbital Diseases and Tumor. He is committed to the clinical treatment of, and basic research on, orbital diseases and tumors, focusing on technological innovation and pathogenesis research in order to diagnose and treat ocular tumors and orbital diseases. He concurrently serves as the President of the Asia-Pacific Society of Ocular Oncology and Pathology, academician of the Academia Ophthalmologica Internationalis, Fellow of the Royal College of Ophthalmologists (UK), and Fellow Ad Hominem of the Royal College of Surgeons of Edinburgh (UK). His awards include: 2 s-place prizes in the National Science and Technology Progress Awards as first-named author, the Ho Leung Ho Lee Foundation Prize for Science and Technology Progress, the AAPPO First Innovator Prize, and the De Ocampo Lecture (the highest academic-achievement award given to ophthalmologists from the Asia-Pacific region).

List of Abbreviations

ΔΨ m Mitochondrial membrane potential AgNP Silver nanoparticle AI Artificial intelligence AML Acute myeloid leukemia ATP Adenosine triphosphate AuNP Gold nanoparticle BTZ Bortezomib BSNP Biodegradable silica nanocapsule CBN Carbon-based nanomaterial CDT Chemodynamic therapy Ce6 Chlorin e6 CM Cell membrane CND Copper nanodot CP Core particle CPCHC cationic poly (vinyl cyclohexene carbonate) CPD CBN-Pluronic F127-DOX CPND Copper peroxide nanodot CPP Cell-penetrating peptide CPTNP Cell-penetrating transformable peptide nanoparticle CQ Chloroquine CS Chondroitin sulfate CT Computed tomography CuSCD CuS nanoparticles integrated with carbon dot DAMP Damage-associated molecular pattern DDS Drug delivery system DLC Delocalized lipophilic cation Dmt Dimethyltyrosine dNase I Deoxyribonuclease I DOX Doxorubicin DSF Disulfiram DUB Deubiquitinating enzyme EGFR Epidermal growth factor receptor EGTA Ethylenebis (oxyethylenenitrilo) tetraacetic acid EMT-NP ER and mitochondrion dual-targeting nanoparticle ER Endoplasmic reticulum FeCO Iron carbonyl ERES ER export site ERGIC ER-Golgi intermediate compartment FA Folic acid FAL Pardaxin GA Golgi apparatus GCA Golgicide A GemE Gemcitabine elailate GENP GA-Pd-L1 −/− exosome hybrid membrane coated nanoparticle Glu Glutaraldehyde GPX4 Glutathione peroxidase 4 GSH Glutathione HA Hyaluronan Hb Hemoglobin HCPT 10-hydroxycamptothecin HSA Human serum albumin HSP Heat shock protein ICD Immunogenic cell death IFN-I Type I interferon IMM Inner mitochondrial membrane IRF-1 Interferon regulatory factor-1 LED Light-emitting diode LMP Lysosomal membrane permeabilization IP3R Inositol 1,4,5-trisphosphate receptor Ir-P PEG-modified Ir NCs LSP Lysosomal sorting peptide Lys Lysine MAM Mitochondrion-associated membrane MFN Mitofusin MNF Metal-nucleic acid frameworks MNAzyme Multicomponent deoxyribozyme MCS Membrane contact site MCU Calcium channel proteins MDR Multidrug resistance MG-2I Diiodine-substituted fluorogenic malachite green derivative MIDRS Mutation-induced drug release system MM Multiple myeloma MPP Mitochondrion-permeable peptide MSN Mesoporous silica nanoparticle mtDNA Mitochondrial DNA mutp53 Mutant p53 ND Nanodroplet nDNA Nuclear DNA NE Nuclear envelope N-GQD Nitrogen-doped graphene quantum dot NIR Near-infrared NLRP3 Nucleotide-binding oligomerization domain-like receptor protein 3 NLS Nuclear localization signal NO Nitric oxide NP Nanoparticle NPC Nuclear pore complex Nup Nucleoporin OMM Outer mitochondrial membrane OXPHOS Oxidative phosphorylation PBS Phosphate buffered saline PCD Programmed cell death PCI Photochemical internalization PD-L1 Programmed death-ligand 1 PDT Photodynamic therapy PEG Polyethylene glycol PEI Polyethylenimine Phe Phenylalanine PROTAC Proteolysis-targeting chimera PTPK PEG-tk-(P18)KLAK PTR Pleurotus tuber-regium PTT Photothermal therapy PTX Paclitaxel RA Retinoic acid RBC Red blood cell RDV Red blood cell-derived vesicle redox Reduction-oxidation RNS Reactive nitrogen species ROS Reactive oxygen species RP Regulatory particle RuR Ruthenium red SAS cells Human tongue squamous carcinoma cells SERCA sarcoplasmic/ER calcium ATPase siRNA Small interfering RNA SNV Single nucleotide variation SREBP1 Sterol regulatory element-binding protein 1 SS Szeto-Schiller STING Stimulator of interferon genes TAM Tumor-associated macrophage TAT Transactivator of transcription TEM Transmission electron micrograph TMV Tumor-derived microvesicle Toy Toyocamycin TPP Triphenylphosphonium TRF2 telomeric repeat-binding factor 2 Tyr Tyrosine UPR Unfolded protein response UPS Ubiquitin-proteasome system US Ultrasound VDAC voltage-dependent anion channel VES Vitamin E succinate ZIF-90 zeolitic imidazole framework-90

Acknowledgements

This work was supported by the 10.13039/501100001809 National Natural Science Foundation of China ( 82388101 , 82203890 , 81930024 , 82271122 , and 12404248 ); the Science and Technology Commission of Shanghai Municipality ( 20DZ2270800 ); and the Shanghai Key Clinical Specialty, Shanghai Eye Disease Research Center ( 2022ZZ01003 ). Jipeng Li acknowledges support from the Shanghai Sailing Program ( 22YF1421500 ). Siwei Yang acknowledges support from the Science and Technology Commission of Shanghai ( 21ZR1482800 ), 10.13039/501100004739 Youth Innovation Promotion Association of the Chinese Academy of Sciences , and the Xinweizhixing Project . Yongqiang Li acknowledges support from 10.13039/501100003399 Science and Technology Commission of Shanghai Municipality ( 23YF1455800 ). We extend our heartfelt gratitude to Prof. Huifang Zhou from Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, for her invaluable contributions to the framework development and manuscript revision of this review. Kexin Tan, Haiyang Zhang, Jianyuan Yang, and Hang Wang contributed equally to this work.

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