Transformative Impact of Nanocarrier-Mediated Drug Delivery: Overcoming Biological Barriers and Expanding Therapeutic Horizons.

Introduction

Drug development and delivery are intricate processes requiring substantial investment in time, resources, and expertise. Exhaustive research efforts have been commenced to identify potential drug targets and delve into the intricate biological mechanisms underlying diseases. [ 1 , 2 ] The primary challenge in drug delivery is addressing medication side effects, which can frequently cause damage to healthy cells and gastrointestinal (GI) issues. Conventional drug delivery methods face significant challenges, such as limited bioavailability, rapid clearance from the body, and nonspecific distribution, all of which reduce treatment efficacy and increase the risk of adverse effects. For instance, these methods often struggle to maintain therapeutic drug levels within the body due to poor absorption and rapid elimination, leading to suboptimal therapeutic outcomes. Additionally, nonspecific drug distribution can harm healthy tissues along with the targeted disease site.

Advanced solutions like nanocarriers offer promising alternatives. These systems can be engineered for triggered release in response to specific stimuli within diseased tissue—such as changes in pH, redox state, or temperature—enabling more precise drug targeting. Despite these advances, effectively delivering therapeutics to target tissues remains challenging due to biological barriers such as shear pressure, protein adsorption, and rapid clearance. Overcoming these hurdles is essential for achieving successful biodistribution and drug delivery. Consequently, there is a strong demand for innovative approaches like nanocarriers that enhance drug stability, improve targeting precision, and extend circulation time, leading to more effective and safer treatments. [ 3 , 4 , 5 , 6 , 7 , 8 ]

Efforts to advance therapeutic progress include the development of drug delivery systems (DDS) capable of sustaining the release of therapeutic molecules. [ 9 , 10 , 11 ] Compared to conventional systems, nano‐DDS offer significant advantages in enhancing therapeutic efficacy. [ 12 , 13 , 14 , 15 ] These systems improve the pharmacokinetics and pharmacodynamics of encapsulated drugs, ensuring better stability and effectiveness. [ 16 , 17 , 18 ] Recent advancements in nanotechnology, particularly innovative nanomaterials, have introduced promising approaches for diagnosing and treating major diseases [ 18 , 19 ] Nanocarriers, typically smaller than 100 nm, have revolutionized the drug delivery field by boosting drug uptake in target tissues, such as tumors, while minimizing off‐target damage. [ 20 ] In 2021, nanomedicines captured a significant market share of $17 billion within the $203.4 billion pharmaceutical industry. With an anticipated compound annual growth rate (CAGR) of 13.4%, this market is expected to reach $433.9 billion. [ 21 , 22 ] Researchers are also exploring polymer–drug conjugates, including those based on polyethylene glycol (PEG) and polymeric micelles, to enhance drug delivery's effectiveness and safety. [ 8 , 23 , 24 ]

Since the early 21st century, nanocarriers have evolved from agricultural use to a diverse range of medical applications, underscoring their importance as a key enabling technology. Nanopharmaceuticals have moved from laboratory proofs of concept to commercially available products, improving the safety and efficacy of drug therapies. [ 25 ] Nanopharmaceuticals have undergone significant evolution, transitioning from early proof‐of‐concept demonstrations in laboratory settings to becoming commercially available products in clinical practice. [ 26 , 27 , 28 ] This evolution has led to substantial improvements in the safety and therapeutic efficacy of encapsulated drugs, making these advanced formulations more effective and reliable for patient care. Emerging technologies to develop nanocarriers, such as nanorobots, when combined with biodegradable polymers, lipid‐based carriers, dendrimers, and micelles nanosystems, hold promise for enhancing drug penetration into diseased tissues. [ 29 , 30 ] These sophisticated platforms enable the precise targeting of therapeutic materials to specific tissues and optimize treatment outcomes while minimizing adverse effects. They possess unique properties, including controlled release, reduced degradation, and increased efficacy. Moreover, their small size enables them to traverse cell membranes and deliver materials to the intracellular compartments. Surface modifications further enhance the affinity of nanocarriers for specific cell surfaces, facilitating the precise delivery of multiple treatments to organs or cells.

This review highlights advances in nanomedicine that could enhance the clinical translation of precision medicines, focusing on improving patient‐specific therapeutic responses. Emphasis is placed on using biomaterials and biomedical engineering innovations to overcome biological barriers and patient variability. The review also addresses the biological constraints that have limited the widespread success of nanocarrier applications and critically evaluates rational nanoparticle (NP) designs aimed at overcoming these challenges. Additionally, it explores the potential of combining artificial intelligence (AI) and nanoscience, particularly in modeling methodologies for nanocarriers in drug delivery. These developments are crucial as they pave the way for the clinical translation of nanocarrier‐based precision treatments in medicine, immunology, and in vivo gene editing.

Organic Nanocarriers

Organic nanobased carrier systems constitute a versatile category of solid particles comprising organic compounds, such as lipids and polymers with diameters ranging from 10 to 1 mm. [ 31 , 32 , 33 , 34 ] Using biopolymers to fabricate these nanocarriers confers several benefits. The synthesis of organic nanocarriers from biopolymers is relatively easy and facilitates efficient production processes. Additionally, these materials exhibit well‐defined functional abilities, allowing their surface properties to be customized for specific applications, such as drug targeting or imaging. Moreover, organic carriers, generally derived from biopolymers, are known for their high biocompatibility within the host organism, minimizing adverse reactions and enabling safe administration in biological systems. They typically demonstrate exceptional stability, ensuring encapsulated cargo preservation during storage and transportation. This stability is essential for maintaining the effectiveness of drugs and the integrity of imaging agents. Biodegradability stands out as another significant advantage of organic carrier fabrication from biopolymers. [ 35 , 36 ] As these materials degrade over time, they are metabolized or eliminated from the body, thereby mitigating the risks of long‐term accumulation and potential toxicity. Various common biopolymers have been employed in organic nanocarrier formulation, including polymers, lipid‐based, dendrimers, nanoemulsions, and nanomicelles ( Figure 1 ). Each of these nanocarrier systems possesses unique characteristics and functionalities that make them suitable for various biomedical applications, including drug delivery, imaging, and diagnostics.

Polymeric Nanocarrier

The use of polymers in the formulation of nanocarriers has significantly enhanced their therapeutic effectiveness by enabling site‐specific targeting of these drugs while minimizing their side effects. Polymers have been employed, either alone or in combination with inorganic nanomaterials, to produce multifunctional DDSs. [ 37 ] Block copolymers, when used in the preparation of drug‐loaded nanocarriers or for surface modification, enhance the interaction between NPs and target tissues, resulting in improved biodistribution, prolonged circulation time, and enhanced uptake. [ 7 , 38 , 39 ] Polymeric nanocarriers are amphiphilic block copolymers with varying hydrophobicity that can be classified into natural and synthetic categories. They can be synthesized using nanoprecipitation or the double‐emulsion method. Given their core–shell structure, they can encapsulate hydrophobic drugs for slow‐release delivery, thereby extending the circulation time within the body. Moreover, the polymeric nanocarrier surfaces can be functionalized with ligands for targeted drug delivery, rendering them highly effective carriers with increased biological activity and bioavailability. [ 40 ]

One of the key advantages of polymeric nanocarriers is their ability to encapsulate various cargo types, including small molecules, nucleic acids (such as DNA and RNA), and proteins (such as peptides and antibodies). This versatility makes them suitable for delivering different types of therapeutics, including chemotherapeutic agents, gene therapies, and biologics. Nanocarriers can achieve drug‐loading percentages ranging from 0.5% to 20% (w/w), depending on the specific agents, the nature of the cargo, and the formulation process. This range allows for the efficient encapsulation of therapeutics while maintaining the stability and integrity of the NPs. [ 7 , 14 , 41 , 42 , 43 ]

Natural polymeric macromolecules, such as chitosan, alginates, dextran, gelatin, and collagen derivatives, have found extensive applications as nanocarrier materials for treating neuroinflammation. [ 40 ] Chitosan, which is derived from crustacean exoskeletons and fungal cell walls, exhibits neuroprotective effects in conditions, such as Alzheimer's disease, by inhibiting various pathological factors. Similarly, alginate extracted from marine brown algae and its derivatives effectively modulate neuroinflammatory responses. Synthetic polymers, including polyesters, polyacrylates, and polycaprolactones, offer controllable synthesis conditions and relatively low‐toxicity profiles compared with natural molecules. Polymeric surface modification strategies have been employed to enhance the half life of drugs in blood circulation and improve controlled drug release over extended periods. Notably, poly‐lactic ‐co ‐glycolic acid (PLGA), FDA approved for human use, is one of the most extensively studied polymers due to its excellent biocompatibility and biodegradability. Innovative polymeric nanocarrier systems, such as PLGA‐PEG conjugated with specific peptides and loaded with therapeutic agents, such as curcumin or epigallocatechin‐3‐gallate, have shown promising results in various neurological conditions, including AD and temporal lobe epilepsy. [ 44 , 45 ] Furthermore, synthetic polymer‐based systems, such as PLGA NPs, loaded with superoxide dismutase or Foxp3 plasmids, have demonstrated neuroprotective effects by reducing apoptosis and inflammatory markers in cerebral ischemic reperfusion injury models. [ 46 , 47 , 48 ]

Liposomes‐Based Nanocarriers

Lipids are amphiphilic molecules that possess a dual nature: one end of the molecule is hydrophilic and the other is hydrophobic (water hating). When exposed to water, lipids undergo self‐assembly because of unfavorable interactions between their hydrophobic segments and the solvent. [ 49 , 50 ] Self‐assembly often results in the formation of liposomes, which are vesicles comprising an aqueous core surrounded by a lipid bilayer resembling a biological membrane. Liposomes have been extensively used as DDSs to enhance the therapeutic efficacy of new drugs through various mechanisms. Liposomes can encapsulate various cargo types, with drug‐loading percentages typically ranging from 0.5% to 20%. This flexibility allows for the efficient encapsulation of therapeutics while maintaining the stability and integrity of the NPs. [ 51 , 52 ] By encapsulating drugs within their lipid bilayers or aqueous cores, liposomes can modify drug absorption, reduce metabolism, prolong the biological half‐life, and mitigate toxicity. This alteration in drug distribution was primarily governed by the properties of the carrier rather than solely by the physicochemical characteristics of the drug substance. Hydrophobic drugs are accommodated within the liposomal bilayer, whereas hydrophilic drugs are trapped within the aqueous core or the bilayer interface. As a result, liposomal formulations have demonstrated enhanced therapeutic efficiency in preclinical models and clinical trials compared to conventional formulations owing to their ability to modulate biodistribution. It can also efficiently encapsulate nucleic acids such as DNA, RNA, and siRNA for gene therapy applications. The lipid bilayers of liposomes protect nucleic acids from degradation by nucleases and facilitate their delivery to target cells for therapeutic gene expression. [ 53 , 54 ] Liposomes are biodegradable, biologically inert, and nonimmunogenic lipids that minimize the risk of immune reactions or adverse effects upon administration. Moreover, these compounds exhibit limited toxicity and do not elicit pyrogenic or antigenic responses. These favorable properties, coupled with the ease of surface modification for targeting specific tissues or cells, render liposomes attractive candidates for drug delivery vehicles compared to other systems, such as NPs and microemulsions. [ 55 ]

Furthermore, the modification of liposome‐based nanocarriers offers versatility and advanced capabilities to deliver various biologically active compounds. [ 56 ] The selection of appropriate preparation methods allows the generation of liposomes with varying sizes, lamellarities, and physicochemical properties, thereby influencing the final amount of the encapsulated drug. The modification of liposomes enables passive or active targeting of specific sites, such as tumors, thus minimizing off‐target effects on nonmalignant cells ( Table 1 ). Studies have demonstrated the efficacy of modified liposomal formulations in enhancing drug therapeutic effects, as evidenced by the increased survival rates in animal models of diseases such as leukemia. “Stealth liposomes” are advanced liposomes that have been stabilized with polyethylene glycol (PEG) to enhance their circulation time in the bloodstream. These liposomes can be further modified to deliver targeted drugs by incorporating monoclonal antibodies, peptides, growth factors, glycoproteins, carbohydrates, or receptor ligands. Additionally, researchers are exploring the use of synthetic polymers like polyvinylpyrrolidone (PVP), polyacrylic acid (PAA), and 1,2‐distearoyl‐sn‐glycero‐3‐phosphatidylethanolamine (DSPE), which are covalently bonded to poly(2‐methyl‐2‐oxazoline) or poly(2‐ethyl‐2‐oxazoline), to further enhance the stability and effectiveness of these liposomal carriers. [ 25 ]

Despite their numerous benefits, liposomes encounter challenges such as degradation, macrophage scavenging, and nonspecific targeting of other tissues. To overcome these limitations, researchers have developed strategies, such as long‐circulation liposomes, actively targeted liposomes, and novel formulations. For example, dopamine‐PEGylated immune‐liposomes have been engineered for Parkinson's disease treatment, demonstrating enhanced brain uptake compared with free dopamine and conventional liposomal formulations. [ 57 ] Tailoring the physicochemical properties of liposomes, such as utilizing pH‐stable lipids such as dipalmitoyl phosphatidylcholine, has enabled the sustained release of drugs and has exhibited therapeutic effects in neuroinflammatory conditions and ischemia‐reperfusion injuries. These advancements underscore the potential of liposomes as effective carriers for drug delivery, paving the way for innovative therapeutic interventions. [ 57 , 58 ]

Solid Lipid‐Based Nanocarrier

To overcome the limitations of polymeric nanocarriers, lipid‐based carriers have emerged as promising alternatives, particularly lipophilic pharmaceuticals. Among these lipid nanocarriers, solid lipid NPs (SLNs) have gained considerable attention from formulators worldwide. [ 59 , 60 ] Developed over the past decade, SLNs represent a novel generation of submicrometer‐sized lipid emulsions, in which the liquid lipid component is replaced with a solid lipid. This substitution offers distinct advantages to SLNs, including small size, large surface area, high drug‐loading capacity, and interactions between phases at the interfaces, making them attractive for enhancing the performance of pharmaceuticals, nutraceuticals, and other materials. Manufactured from either synthetic or natural lipids, SLNs feature a lipid core that remains in a solid state at both room and body temperatures. [ 61 ] Compared with cationic liposomes, SLNs are generally considered less toxic and are recognized as safe for human use. These submicrometer colloidal carriers comprise physiological lipids dispersed in water or an aqueous surfactant solution, offering physiological tolerance and superior drug delivery efficiency compared to other lipid‐based nanocarrier formulations. [ 62 , 63 , 64 ]

SLNs have garnered significant interest as novel colloidal drug carriers for intravenous applications and have demonstrated superior efficacy in various therapeutic applications. For example, SLNs loaded with curcumin demonstrated enhanced anti‐amyloid‐beta, anti‐inflammatory, and neuroprotective effects compared to traditional curcumin formulations in mouse models of AD. Additionally, sesamol‐loaded SLNs have been found to alleviate oxidative stress and mitigate neuroinflammation and memory deficits in experimental models of neurodegenerative diseases. [ 65 ]

Dendrimers

Dendrimers, a class of highly organized macromolecules synthesized through the repetitive chemical reactions of core structures, have been extensively investigated. These dendrimers serve as highly effective carriers for delivering drugs, genes, and proteins across barriers through mechanisms such as covalent bonding, ion interactions, or adsorption. [ 66 , 67 , 68 ] Their advantages include precisely controlled biodistribution and pharmacokinetics, notable structural and chemical uniformity aiding reproducibility, the ability to interact with various compounds or ligands to enhance solubility and specificity, and multifunctionality due to abundant surface groups. The drug‐loading capacity of dendrimers typically falls within 1%–5%, allowing for efficient encapsulation while maintaining the structural integrity and stability of the dendrimer–drug complexes. [ 69 , 70 ] The administration of specific dendrimers in animal models results in transient elevations in liver enzyme levels and leukocyte infiltration. [ 71 , 72 ] However, other studies have highlighted the beneficial effects of dendrimers on human health. Dendrimer‐based therapies have demonstrated promise in addressing conditions, such as neuroinflammation and cerebral palsy, by elevating antioxidant levels and mitigating neuroinflammation. [ 73 , 74 , 75 ] Dendritic polyglycerol sulfates have emerged as potent inhibitors of inflammation and complement activation. Studies have indicated that dPGS can disrupt the formation of amyloid‐beta fibrils, decrease the production of neuroinflammatory lipocalin‐2, and normalize impaired neuroglial cells, suggesting potential applications in treating neuroinflammatory conditions and neurotoxicity associated with neurodegenerative diseases, such as AD. [ 76 , 77 , 78 , 79 ]

Poly (amidoamine) dendrimers are used as nanocarriers due to the presence of tertiary amine groups at their branching points. The metal ions introduced into aqueous dendrimer solutions form complexes with these amine groups, which are then reduced to form nanocarriers encapsulated within the dendrimer structure. Various dendrimeric formulations have been employed as nanodrugs for treating diverse diseases, including antiviral formulations containing polylysine dendrimers with sulfonated naphthyl groups, antibacterial agents comprising PPL dendrimers with tertiary alkylammonium groups, and chitosan dendrimer hybrids used for antibacterial purposes. When combined with anti‐inflammatory and antioxidant drugs, advanced poly (amidoamine) dendrimers exhibit the potential to attenuate inflammation in traumatic brain injury by inhibiting proinflammatory cytokines and reducing NF‐κB activation. Similarly, dendrimer‐based N‐acetyl‐L‐cysteine formulations have been shown to increase intracellular antioxidant levels and prevent excitotoxicity in microglia and astrocytes. Dendrimeric formulations incorporated into hydrogels function as crosslinked networks that expand in an aqueous solution. These formulations, which are often modified with polyethylene glycol groups, are useful for cartilage tissue engineering, ocular injury sealing, and targeted drug delivery. Additionally, dendrimers have shown promise in transdermal drug delivery by enhancing solubility and plasma circulation, forming complexes with drugs like nonsteroidal anti‐inflammatory agents to enhance skin permeation and acting as permeation enhancers. [ 66 , 73 ]

Nanoemulsions

Nanoemulsions are colloidal dispersions composed of two immiscible liquids stabilized by surfactants. Typically, an nanoemulsion (NE) comprises water, oil, and emulsifiers in appropriate proportions. NEs offer several advantageous properties, such as excellent biocompatibility, kinetic stability, cell transport facilitation through paracellular and transcellular pathways, and protection against hydrolysis and enzymatic degradation of residues. [ 80 ] These versatile systems are adept at encapsulating components dissolved in the dispersed phase. Direct systems such as oil‐in‐water nanoemulsions are suitable for encapsulating hydrophobic components, whereas inverse systems facilitate hydrophilic cargo encapsulation. NEs can be administered via the nasal, ocular, oral, and intravenous routes.

Chitosan‐coated rosmarinic acid nanoemulsions have demonstrated protective effects by inhibiting cellular death and restoring the astrocyte redox state during lipopolysaccharide‐induced neuroinflammation and oxidative stress in astrocytes. Studies demonstrated that siRNA nanoemulsions markedly reduced the levels of TNF‐α, a pro‐inflammatory signaling molecule. Therefore, nanoemulsions encapsulated with TNF‐α siRNA hold promise as potential candidates for treating neuroinflammation. [ 81 ] Ropinirole, a dopamine agonist used in combination therapy with levodopa for Parkinson's disease, has limitations due to its low bioavailability and short half life. Indeed, modification of the ropinirole NE gel for transdermal delivery has shown improved drug absorption and reduced skin irritation and toxicity compared with ropinirole alone.

Micelles as Nanocarriers

Micelles, which are self‐assembling nanosized colloidal particles characterized by a hydrophobic core and hydrophilic shell, serve as effective pharmaceutical carriers for water‐insoluble drugs, offering several desirable properties. Amphiphilic copolymers, composed of hydrophobic and hydrophilic blocks, are gaining attention as compounds capable of forming micelles. Polymeric micelles, including lipid‐core micelles formed by the conjugation of soluble copolymers with lipids, exhibit high stability, both in vitro and in vivo, along with good biocompatibility. They can solubilize various poorly soluble pharmaceuticals, many of which are undergoing preclinical and clinical trials. [ 82 , 83 ]

The most commonly used hydrophilic segment in micelles for drug delivery is poly(ethylene glycol) (PEG), which typically has a molecular weight of 2–15 kDa. PEG, known for its high water solubility, nontoxicity, and neutral charge, forms a hydrophilic corona on the micelle surface, minimizing nonspecific interactions with blood components and prolonging circulation time. Besides PEG, other polymers such as poly(N‐vinyl pyrrolidone) (PVP) and poly(N‐isopropyl acrylamide) have also been employed as hydrophilic portions of the micelles. Another type of polymeric micelle utilizes lipids as the hydrophobic core, as exemplified by PEG‐diacyllipid conjugates synthesized by Torchilin's group. These micelles exhibited strong hydrophobic interactions between the double acyl chains, resulting in stable micelles with low critical micelle concentration values. They can effectively solubilize various poorly water‐soluble drugs and demonstrate favorable stability, prolonged circulation in the blood, and tumor accumulation via enhanced permeability and retention. [ 84 ] Further development of micellar systems composed of PEG–cholic acid conjugates, which exhibit a high loading capacity for drugs, such as paclitaxel. These micelles have demonstrated improved anticancer efficacy and reduced toxicity compared with conventional formulations in preclinical models and clinical trials. Additionally, micellar carriers like PEG2K–cholic acid have shown higher drug loading capacities and sustained drug release profiles, offering promising prospects for drug delivery applications. [ 84 ] Yokoyama et al. reported that adriamycin‐conjugated polyethylene glycol–poly(aspartic acid) block copolymers (PEG‐P[Asp(ADR)]) formed micelles in aqueous solution and demonstrated significant antitumor activity in vivo. [ 85 ] However, this study did not analyze the ratio of chemically or physically entrapped adriamycin, and certain amounts of adriamycin derivatives were incorporated into the micelles as impurities. These impurities can cause adverse effects.

Micelles, which are self‐assembling nanosized colloidal particles characterized by a hydrophobic core and hydrophilic shell, serve as effective pharmaceutical carriers for water‐insoluble drugs, offering various desirable properties. Amphiphilic copolymers, composed of hydrophobic and hydrophilic blocks, are gaining attention as compounds capable of forming micelles. Polymeric micelles, including lipid‐core micelles formed by the conjugation of soluble copolymers with lipids, exhibit high stability, both in vitro and in vivo, along with good biocompatibility. They can solubilize various poorly soluble pharmaceuticals, many of which are undergoing preclinical and clinical trials. [ 82 , 83 ]

The most commonly used hydrophilic segment in micelles for drug delivery is PEG, which typically has a molecular weight of 2–15 kDa. PEG, known for its high water solubility, nontoxicity, and neutral charge, forms a hydrophilic corona on the micelle surface, minimizing nonspecific interactions with blood components and prolonging circulation time. In addition to PEG, other polymers such as PVP and poly(N‐isopropyl acrylamide) have also been employed as hydrophilic portions of the micelles. Another type of polymeric micelle utilizes lipids as the hydrophobic core, as exemplified by PEG–diacyllipid conjugates synthesized by Torchilin's group. These micelles exhibited strong hydrophobic interactions between the double acyl chains, resulting in stable micelles with low critical micelle concentration values. They can effectively solubilize various poorly water‐soluble drugs and demonstrate favorable stability, prolonged circulation in the blood, and tumor accumulation via enhanced permeability and retention. [ 84 ] Further development of micellar systems composed of PEG‐cholic acid conjugates, which exhibit a high loading capacity for drugs, such as paclitaxel. These micelles have demonstrated improved anticancer efficacy and reduced toxicity compared with conventional formulations in preclinical models and clinical trials. Additionally, micellar carriers like PEG2K‐ cholic acid have shown higher drug loading capacities and sustained drug release profiles, offering promising prospects for drug delivery applications. [ 84 ] Yokoyama et al. reported that adriamycin‐conjugated polyethylene glycol–poly(aspartic acid) block copolymers (PEG‐P[Asp(ADR)]) formed micelles in aqueous solution and demonstrated significant antitumor activity in vivo. [ 85 ] However, this study did not analyze the ratio of chemically or physically entrapped adriamycin, and certain amounts of adriamycin derivatives were incorporated into the micelles as impurities. These impurities can cause adverse effects.

Polymeric Lipid Hybrid Nanocarriers

The formation of stable hybrid vesicles in polymeric–lipid hybrid nanocarriers is primarily determined by the differences in chemical composition and the size of the hydrophobic segments between polymers and lipids ( Figure 2 ). This hybrid nanocarrier system integrates the essential features of both polymers and lipids into a single, unified structure, [ 86 ] allowing for the creation of various combinations that effectively address the limitations of individual components within the hybrid framework. Polymers play a crucial role in ensuring sustained drug release, enhancing the architectural stability and durability of the hybrid system. Meanwhile, lipids, with their biomimetic properties, significantly improve the drug‐loading capacity of these carriers. Compared with nanomaterials composed solely of either polymers or lipids, hybrid particles demonstrate superior and prolonged efficacy in vivo. [ 87 ]

Furthermore, the vesicular structures that emerge are influenced by factors such as the polymer‐to‐lipid molar ratio and the thermodynamic phase of the phospholipids. These structures can range from a homogeneous mixture of polymers and lipids to distinct microdomains rich in either polymer or lipid. [ 88 ] For instance, adjusting the polymer/lipid molar ratio can result in vesicles with varying internal architectures. A higher polymer content may lead to thicker, more stable vesicles, while a higher lipid content might produce more flexible structures with specific biological functionalities.

The thermodynamic phase of the lipid component, often defined by the lipid's main chain transition temperature ( T m ), is a crucial factor in determining membrane properties. Below T m , lipids exist in a gel‐like state, resulting in more rigid and ordered membrane structures. Above T m , lipids transition to a fluid, liquid‐crystalline state, leading to more flexible and dynamic membranes. In hybrid vesicles, this phase behavior is comparable to that observed in mixed liposomes made from lipids with varying T m values. [ 89 , 90 ]

The interaction between polymers and lipids in hybrid vesicles is significantly influenced by the size mismatch between polymer chains and lipid tails. Liposomes typically have a membrane thickness of 3–5 nm, while polymersomes can vary between 5 and 50 nm. When there is a notable size disparity between the polymer and lipid components, it can create high line tension at the interface between lipid‐rich and polymer‐rich regions. This tension arises from the thickness mismatch, which can expose hydrophobic polymer segments to the aqueous environment, increasing the system's overall energy. [ 88 ]

To mitigate this energetic penalty, the system may adopt one of two possible strategies: conformational adaptation or calescence into larger domains. In conformational adaptation, the polymer chains at the boundary between lipid and polymer domains may undergo elastic deformation. [ 88 , 91 , 92 ] This deformation helps to reduce the line tension but comes at the cost of reduced entropy, as the number of possible conformations for the polymer chains decreases. This situation is somewhat analogous to the elastic deformation observed in lipid membranes with coexisting phases, where the membrane bends to accommodate different lipid compositions. For example, in a hybrid vesicle composed of a rigid polymer like polystyrene and a fluid lipid like dioleoylphosphatidylcholine (DOPC), the polymer may deform at the boundary with the lipid domain to minimize exposure to water, resulting in a more stable interface.

Alternatively, if the conformational adaptation of the polymer chains is insufficient to stabilize the structure, the system may allow the lipid or polymer domains to grow larger. This reduces the overall interface area between mismatched regions, thus minimizing the line tension and associated energy cost. In a system where the polymer chains are too rigid or too large to deform easily, such as in hybrid vesicles made with a block copolymer like polyethylene glycol–polylactic acid (PEG–PLA) and a lipid like dipalmitoylphosphatidylcholine (DPPC), the vesicle might form larger lipid domains surrounded by polymer regions to reduce boundary exposure.

The ability of a hybrid vesicle to adapt to various conditions is largely determined by the molecular characteristics of the polymer, including its molar mass, chain length, and the rigidity of its hydrophobic backbone. If the polymer chains are too rigid or if there is a significant size mismatch, the system may fail to form stable domains, resulting in a homogeneous mixture where the components are evenly distributed throughout the vesicle. A study that addressed the line tension in hybrid polymer/lipid vesicles found that the values are comparable to those observed in multiphase lipid vesicles. The authors emphasized that determining the line tension in polymer/lipid hybrid systems is crucial for better understanding the structure and properties of these hybrid membranes. [ 93 ]

By integrating polymers and lipids into a single entity, hybrid structures present significant potential as highly effective drug delivery carriers [ 94 , 95 ] ( Figure 3 ). With precise engineering and formulation techniques, these hybrid structures can be tailored to optimize drug delivery for various therapeutic applications ( Table 2 ).

Polymer Core–Lipid Shell Hybrid Carriers

Hybrid polymer core–lipid shell nanocarriers represent a significant advancement in drug delivery technology and have been extensively studied owing to their promising applications. These nanocarriers comprise a polymeric core surrounded by a lipid shell that combines the advantages of both materials. Initially used in biomedical and biotechnological devices, hybrid nanocarriers were created by mixing liposomes with polymeric nanocarriers, resulting in a composite structure with a polymeric core and a lipid coating. Typically, one or two lipid layers envelop the polymer backbone, with water or a buffer filling the gaps. These lipid shells are composed of either cationic or anionic phospholipids that facilitate electrostatic interactions between oppositely charged components. Three main layers were identified in these hybrids: a biodegradable hydrophobic polymer (such as PLGA), a lipid–PEG conjugate shell capable of incorporating hydrophilic drugs, and an intermediate lipid layer that acts as a barrier to prevent leakage or water penetration. This layered structure ensures robust formulation integrity. [ 87 , 96 ]

Although the loading of water‐soluble ionic drugs presents challenges, hydrophobic drugs can be readily incorporated into hybrid nanocarriers. However, the complex formation of ionic drugs with counterion polymers may improve their loading efficiency. Additionally, the outer lipid shell enhances the integrity of the system. Researchers have demonstrated the versatility of these polymer–lipid hybrids by modifying SLNs to encapsulate positively charged hydrophilic drugs within an anionic polymer matrix. For example, salidroside, a water‐soluble antitumor compound, was successfully entrapped in a polymeric core–lipid shell (PLGA–PEG–PLGA) system, resulting in improved drug entrapment capacity, enhanced tumor cell uptake, and smaller particle size. [ 94 ] Similarly, enoxaparin was encapsulated in alginate‐coated chitosan nanocarriers, where the cationic polymer chitosan acted as a charge stabilizer.

Polymer‐Caged Nanobins

Polymer‐caged nanobins represent a sophisticated approach for achieving desired properties in DDSs, such as enhanced drug release, improved stability, and minimized leakage. [ 97 ] These particles were coated with additional polymer layers on the outside, offering opportunities for customization and functionality. The outer layers of polyacrylic acid can be used to introduce specific surface features. By attaching various linkers via carboxylic groups to these polymers, pH‐sensitive reactions can be achieved. [ 98 , 99 ] The preparation of liposomes with polymers involves the modification of their surface properties to attain optimal characteristics. Initially, the liposomes were created as base structures. Subsequently, polymeric coats, including cholesterol‐functionalized polyacrylic acid, were applied to the surfaces. This process involves the addition of carboxylate groups to the liposomal surfaces to enhance their functionality. The drug‐release profiles of these systems can be tailored to meet specific requirements. Another strategy involves using pH‐responsive crosslinked polymers to shield the liposome environment. [ 100 ] This polymer coating offers significant advantages, including the protection of liposomes, increased durability, minimized drug degradation due to leakage, and enhanced drug release at targeted sites.

Monolithic LPNPs‐Mixed Lipid–Polymer

Monolithic lipid polymer nanoparticles (LPNPs)/mixed lipid polymers represent an innovative strategy for nanocarrier formulation, offering a unique combination of lipid and polymer components for drug delivery applications. [ 101 ] These nanocarriers were designed with lipids dispersed within a polymer matrix, resembling colloidal carriers tailored for efficient drug distribution throughout the body. These nanocarriers, which are composed of a combination of copolymers with both hydrophilic and hydrophobic segments, as well as lipids, have amphiphilic features that are required for drug encapsulation and delivery. These hybrid nanocarriers, such as liposomes, which are composed of phospholipids that form vesicular structures resembling cell membranes, exploit the self‐assembling characteristics of phospholipids. However, unlike conventional liposomes, the structural configuration of monolithic LPNPs/mixed lipid–polymer NPs offers distinct advantages and challenges. While liposomes can be easily modified by PEG to enhance their stability and circulation time in the bloodstream, the incorporation of PEG‐lipid conjugates at high densities may compromise the structural integrity of phospholipids within these hybrid nanocarriers. This limitation arises from the tendency of phospholipids to form micelles rather than maintaining vesicular structures under such conditions. Despite this challenge, monolithic LPNPs‐mixed lipid–polymer NPs hold promise as versatile drug delivery vehicles. [ 102 , 103 ] By combining the benefits of lipids, such as biocompatibility and membrane‐mimicking properties, with those of polymers, such as controlled release and stability, they offer a platform for targeted and sustained drug delivery.

Lipid Bilayer‐Coated Nanocarriers

Lipid bilayer‐coated NPs represent an innovative approach for enhancing the stability and functionality of DDSs, particularly in cases where polyethylene glycol alone may not be sufficient for in vivo particle stabilization. These nanocarriers are coated with lipid bilayers derived from red blood cell membranes, offering unique advantages in terms of biocompatibility and prolonged drug release. The process of creating lipid bilayer‐coated nanocarriers typically involves the heat treatment of red blood cells (RBCs) to generate membrane‐derived particles. During this process, polymeric nanocarriers are encapsulated within lipid bilayers derived from erythrocyte membranes. This encapsulation process effectively targets the drug within the polymeric nanocarriers, providing lipid‐coated nanocarriers with enhanced biological surface strength and maximum in vivo stability. Encapsulation of polymeric nanocarriers within lipid bilayers mimics the complex surface chemistry of RBCs, offering a biomimetic environment for drug delivery. The drug payload is enclosed within vesicles formed by the erythrocyte membrane, enabling prolonged drug release from the lipid bilayer. The dense lipid barrier contributes to a slower release profile, ensuring sustained therapeutic efficacy. However, the presence of various blood type antigens in RBC membranes can pose challenges in terms of crossmatching during blood transfusion. [ 104 , 105 , 106 ] Despite these considerations, lipid bilayer‐coated nanocarriers have significant potential as effective and biocompatible drug delivery vehicles, offering controlled release and enhanced stability for various therapeutic applications.

Hollow‐Core Nanoparticles/Lipid–Polymer–lipid Nanocarriers

These nanocarriers have concentric structures with an innermost hollow layer of lipids, a middle layer of polymers, and an outermost lipid–PEG layer. Fabricating these lipid–polymer–lipid nanocarriers typically involves a double‐emulsification solvent evaporation method. [ 95 , 107 ] During this process, lipids and polymers are emulsified to form concentric layers, resulting in polymer lipoplexes and properties similar to poly lactic ‐co ‐glycolic acid nanocarriers. The outer lipid–PEG‐conjugated layer enhanced in vivo stability, whereas the inner cationic lipid layer enabled the encapsulation of anionic drugs. This design allows the codelivery of multiple medications, making it suitable for applications such as multidrug‐resistant cancer therapy.

Overview of Biological Barriers and Overcomes Through Nanocarriers

The effective delivery of therapeutics to target tissues remains a major challenge in drug development. Biological barriers include the blood–brain barrier (BBB), skin layers, intercellular barrier, tumor microenvironment (TME), and epithelial barrier ( Figure 4 ). Nanocarriers offer a promising solution to overcome these barriers owing to their small size, high surface area‐to‐volume ratio, and customizable surface properties. Achieving successful biodistribution and drug delivery necessitates overcoming physiological and biological hurdles such as shear pressure, protein adsorption, and rapid clearance. These barriers undergo alterations in disease states, rendering them even more difficult to overcome using conventional one‐size‐fits‐all approaches. Changes in biological barriers are manifested at the systemic, microenvironmental, and cellular levels, exhibiting variability on a patient‐to‐patient basis. This variability makes it challenging to comprehensively identify and characterize these barriers. Nonetheless, understanding the biological barriers encountered by patients at a general level as well as on an individualized basis is crucial for developing optimal NP platforms. Achieving site‐specific drug delivery remains an elusive goal until the nanocarrier design effectively addresses the multitude of biological barriers encountered during drug administration. Although nanomedicine and nanodelivery systems represent burgeoning fields, overcoming these barriers and integrating unique design elements will pave the way for a new generation of nanotherapeutics.

Blood–Brain Barrier and Role of Carriers

The BBB is a highly specialized barrier that separates circulating blood from the extracellular fluid in the brain. Composed of endothelial cells, tight junctions, pericytes, and astrocytes, the BBB tightly regulates the passage of molecules into the central nervous system (CNS) [ 49 , 108 , 109 ] ( Figure 5 ). The impermeability of the BBB poses a significant challenge in the treatment of neurological disorders because it restricts the delivery of therapeutic agents to the brain parenchyma. [ 110 , 111 ] The efficient delivery of nanocarriers to the CNS requires intricate mechanisms involving receptor‐mediated endocytosis by endothelial cells of the BBB, followed by exocytosis. [ 49 ] The strategy for accessing brain tissue is receptor‐mediated transcytosis, which exploits receptors overexpressed in the BBB [ 112 , 113 ] ( Table 3 ). RMT triggers endocytosis via clathrin‐coated pits or caveolae, similar to adsorption‐mediated transcytosis (AMT). Upon internalization, nanoparticles navigate various intracellular pathways influenced by their size, charge, composition, and ligand conjugation. Commonly targeted receptors that facilitate RMT through the BBB include transferrin, lactoferrin, low‐density lipoprotein (LDL), and nicotinic acetylcholine. Moreover, insulin and insulin‐like growth factor receptors in the brain capillary endothelial cells offer intriguing prospects. This approach was explored in rhesus monkeys, where pegylated immune liposomes, conjugated with monoclonal antibodies against the human insulin receptor, demonstrated widespread β‐galactosidase expression in the primate brain. [ 113 ]

The primary role of the LDL receptor is the clearance of LDL particles from the bloodstream through clathrin‐mediated endocytosis, a process crucial for regulating cholesterol levels and preventing atherosclerosis. [ 114 , 115 ] Interestingly, brain endothelial cells also express high LDL receptor levels, along with LDLR‐related protein 1 (LRP1) and very LDL receptors, making them potential targets for drug delivery across the BBB. Apolipoprotein E (ApoE), a soluble apolipoprotein that binds to LDL receptors, is a compelling target for facilitating BBB passage. By leveraging this interaction, researchers developed ApoE‐coated nanosystems to enhance drug delivery to the brain. Several studies have demonstrated the efficacy of ApoE‐coated nanocarriers in facilitating BBB traversal and improving the brain permeability of therapeutic agents. [ 116 , 117 ] Neves et al. utilized solid lipid nanocarriers functionalized with ApoE using biotin–avidin interactions to transport resveratrol, a bioactive compound with neurological benefits, across the BBB. [ 118 ] Their findings revealed a significant increase in barrier transit for functionalized nanocarriers compared to that for nonfunctionalized nanocarriers. Similarly, Zensi et al. demonstrated the brain‐targeting capabilities of albumin nanocarriers bound to ApoE in intravenously injected mice. Coated NPs are specifically localized in the brain capillary endothelial cells and neurons, highlighting their potential for targeted drug delivery to the brain. [ 119 ]

The transferrin receptor (TfR), a membrane protein comprising two glycosylated subunits, binds to circulating transferrin and triggers endocytosis via clathrin‐coated pits. This is considered a promising approach for facilitating drug delivery across the BBB. TfR expression in brain endothelial cells is an alternative target for mediating BBB passage and drug delivery to the brain. Nanocarriers containing transferrin have emerged as a strategy to enhance the brain uptake of therapeutic agents. Numerous studies have demonstrated the effectiveness of transferrin‐functionalized nanocarriers in traversing the BBB and delivering drugs to the brain. [ 120 , 121 ] For example, cationic lipid nanocarriers incorporating transferrin exhibit successful transcytosis through brain microvascular endothelial cell monolayers in vitro, highlighting their potential for BBB penetration. Transferrin‐targeted nanocarriers have shown promise for brain cancer therapy. [ 122 ] Liposomes conjugated with transferrin successfully targeted brain tumor cells in preclinical models, offering a potential strategy for precise drug delivery to tumor sites. Multifunctional nanocarriers combining magnetic, polymeric, and mesoporous silica components facilitate the delivery of chemotherapeutic drugs to brain cancer xenografts, resulting in significant tumor growth inhibition.

Lactoferrin and transferrin exhibit differences in their receptor‐binding properties that can be attributed to subtle structural variations in their lobes and interlobe linkers. Interestingly, lactoferrin demonstrates higher brain uptake than transferrin and other receptor‐targeting agents, offering potential advantages in enhancing drug delivery to the brain. [ 123 ] Studies have demonstrated the use of lactoferrin‐functionalized nanocarriers in various therapeutic applications, including cancer, neurodegenerative diseases, and gene therapy. Nanocarriers coated with lactoferrin have been shown to enhance brain uptake and bioavailability in preclinical models, indicating their potential for targeted drug delivery to the brain. In the treatment of neurodegenerative diseases, such as AD, lactoferrin‐conjugated PEG‐PLGA NPs have shown promise and improved brain delivery. [ 124 , 125 ] Nanocarriers loaded with neuroprotective peptides or therapeutic molecules have demonstrated efficacy in rescuing neuronal function and improving memory in animal models of AD. The combination of LF‐mediated brain delivery with therapeutic interventions has yielded promising results in preclinical PD models. Nanocarriers loaded with therapeutic agents and functionalized with lactoferrin have been shown to rescue neuronal function and attenuate disease progression in animal models of PD.

Skin Barrier and Overcome by Nanocarriers

Nanoscale carrier systems have been extensively studied for their interactions with the skin and ability to enhance drug penetration. However, the increased production of engineered nanoscale materials necessitates a thorough safety evaluation. The success of drug delivery and risk assessment relies on the ability of these carriers to overcome the skin barrier and reach deeper tissue layers. Delivery through the skin can occur via intercellular, transcellular, or appendageal routes. Among these, hair follicles are particularly promising targets for NP carrier systems. The stratum corneum (SC) is the primary barrier to absorption. Despite their relatively small surface areas, skin appendages play a significant role and can potentially be targeted for directed delivery because of their depth. [ 126 , 127 ]

Among various pathways involved in skin permeation, the transcellular route is the most direct and rapid. However, traversing this pathway poses challenges as the NPs encounter both lipophilic barriers, such as the cell membrane and lipid matrix, and hydrophobic barriers within the skin cells. The intercellular route has emerged as the primary pathway for nanocarrier penetration and involves diffusion between intercellular lipids. Successful navigation through this route requires careful consideration of the size and mechanical properties of the nanocarriers because flexibility is essential. [ 127 , 128 ] The follicular pathway is a commonly proposed method for highly rigid nanocarriers to penetrate the skin. This approach involves delivering medications directly through the hair follicles and glandular ducts. Nanocarriers that accumulate within the hair follicle canal exhibit depot activity, enabling sustained drug release. The size of the applied nanocarriers is crucial, as it affects the penetration depth and facilitates the selective targeting of specific compartments within the hair follicle. Toll et al. indicated that the use of smaller NPs leads to an increased penetration depth in terminal hair follicles. Similarly, studies by Roman et al. utilizing animal models demonstrated that ≈20 nm NPs penetrate deeper than polystyrene particles of ≈ 200 nm. [ 129 ]

Polymeric materials are promising and are mostly used as carrier agents for drug delivery because of their intrinsic biocompatibility and biodegradability. [ 128 , 130 ] Numerous studies on the penetration of drugs encapsulated in polymer‐based particles have highlighted the significant differences between conventional and nanoparticulate formulations. Liposomes comprise a closed bilayer of phospholipids and feature hydrophobic (lipid layer) and hydrophilic compartments (inner volume of the liposome). Their versatility in incorporating a wide variety of drugs, along with their inherent biocompatibility linked to natural phospholipids, makes them a major group of nanoparticulate carriers for cosmetic and therapeutic applications. Due to their larger size (≥50 nm) compared to skin openings, passive penetration of liposomes is hindered, necessitating a substantial driving force to propel them through the skin. Cevc and colleagues proposed a mechanism based on hydration gradient‐driven transport to elucidate the observed dermal penetration, wherein the differential activity of water on the two barrier sides facilitates aggregate migration. SLNs, composed of physiological solid lipids produced through high‐pressure homogenization, lead to enhanced drug permeation when applied to the skin. However, this increased drug absorption is attributed not to penetrating particles, but to the occlusive effect resulting from surface coverage. [ 126 ] SLNs enhance the chemical stability of the encapsulated drugs by protecting them from hydrolysis and oxidation in a solid matrix. Additionally, SLNs contain physiological excipients that are generally recognized as safe, such as glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, trimyristin, tripalmitin, tristearin, or wax cetyl palmitate, making them acceptable from a cosmetic standpoint and well tolerated for topical application on the skin. [ 131 , 132 , 133 ]

Combining nanoemulsions with microneedles is a promising approach for delivering drugs that face challenges in diffusion across the skin barrier. Several examples highlight the effectiveness of this strategy, including the macroflux transdermal technology developed by Zosano (Mountain View, CA, United States) and the MicronJet developed by NanoPass Technologies (Haifa, Israel). These innovative technologies leverage the advantages of nanoemulsions, which enhance the solubility and bioavailability of drugs and the precise delivery capabilities of microneedles to facilitate medication administration through the skin. By overcoming the limitations of traditional drug delivery methods, such as poor skin permeability, these coupled systems offer a promising solution for improving the efficacy and efficiency of transdermal drug delivery. [ 134 ] Nanoscale carrier systems have been extensively studied for their interaction with the skin and ability to enhance drug penetration. However, the increased production of engineered nanoscale materials necessitates a thorough safety evaluation. The success of drug delivery and risk assessment relies on the ability of these carriers to overcome the skin barrier and reach deeper tissue layers. Delivery through the skin can occur via intercellular, transcellular, or appendageal routes. Among these, hair follicles are particularly promising targets for NP carrier systems. The SC is the primary barrier to absorption. Despite their relatively small surface areas, skin appendages play a significant role and can potentially be targeted for directed delivery because of their depth. [ 126 , 127 ]

Among various pathways involved in skin permeation, the transcellular route is the most direct and rapid. However, traversing this pathway poses challenges as the NPs encounter both lipophilic barriers, such as the cell membrane and lipid matrix, and hydrophobic barriers within the skin cells. The intercellular route has emerged as the primary pathway for nanocarrier penetration and involves diffusion between intercellular lipids. Successful navigation through this route requires careful consideration of the size and mechanical properties of the nanocarriers because flexibility is essential. [ 127 , 128 ] The follicular pathway is a commonly proposed method for highly rigid nanocarriers to penetrate the skin. This approach involves delivering medications directly through the hair follicles and glandular ducts. Nanocarriers that accumulate within the hair follicle canal exhibit depot activity, enabling sustained drug release. The size of the applied nanocarriers is crucial, as it affects the penetration depth and facilitates the selective targeting of specific compartments within the hair follicle. Toll et al. indicated that the use of smaller NPs leads to an increased penetration depth in terminal hair follicles. Similarly, studies by Roman et al. utilizing animal models demonstrated that ≈20 nm NPs penetrate deeper than polystyrene particles of ≈200 nm. [ 129 ]

Polymeric materials are promising and are mostly used as carrier agents for drug delivery because of their intrinsic biocompatibility and biodegradability. [ 128 , 130 ] Numerous studies on the penetration of drugs encapsulated in polymer‐based particles have highlighted the significant differences between conventional and nanoparticulate formulations. Liposomes comprise a closed bilayer of phospholipids and feature hydrophobic (lipid layer) and hydrophilic compartments (inner volume of the liposome). Their versatility in incorporating various drugs, along with their inherent biocompatibility linked to natural phospholipids, makes them a major group of nanoparticulate carriers for cosmetic and therapeutic applications. Due to their larger size (≥50 nm) compared to skin openings, passive penetration of liposomes is hindered, necessitating a substantial driving force to propel them through the skin. Cevc and co‐workers proposed a mechanism based on hydration gradient‐driven transport to elucidate the observed dermal penetration, wherein the differential activity of water on the two barrier sides facilitates aggregate migration. SLNs, composed of physiological solid lipids produced through high‐pressure homogenization, lead to enhanced drug permeation when applied to the skin. However, this increased drug absorption is attributed not to penetrating particles, but to the occlusive effect resulting from surface coverage. [ 126 ] SLNs enhance the chemical stability of the encapsulated drugs by protecting them from hydrolysis and oxidation in a solid matrix. Additionally, SLNs contain physiological excipients that are generally recognized as safe, such as glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, trimyristin, tripalmitin, tristearin, or wax cetyl palmitate, making them acceptable from a cosmetic standpoint and well tolerated for topical application on the skin. [ 131 , 132 , 133 ]

Combining nanoemulsions with microneedles is a promising approach for delivering drugs that face challenges in diffusion across the skin barrier. Several examples highlight the effectiveness of this strategy, including the macroflux transdermal technology developed by Zosano (Mountain View, CA, United States) and the MicronJet developed by NanoPass Technologies (Haifa, Israel). These innovative technologies leverage the advantages of nanoemulsions, which enhance the solubility and bioavailability of drugs and the precise delivery capabilities of microneedles to facilitate medication administration through the skin. By overcoming the limitations of traditional drug delivery methods such as poor skin permeability, these coupled systems offer promising solutions for improving the efficacy and efficiency of transdermal drug delivery. [ 134 ]

Intercellular Barrier and Functional Role of Nanocarriers

Subcellular targeting is critical for achieving efficient and specific treatments for various diseases. This targeting is particularly crucial in conditions such as cancer, Alzheimer's disease, diabetes, infectious diseases, and autoimmune disorders, where the precise delivery of drugs to specific organelles within cells can significantly enhance therapeutic efficacy or alleviate symptoms. [ 135 , 136 ] However, the low pH and abundance of enzymes in the endosomes and lysosomes pose challenges. Thus, drug molecules that end up in these compartments may undergo degradation or be distributed nonspecifically, reducing their effectiveness. [ 137 , 138 ] The ability of nanomaterials to overcome these subcellular barriers has spurred the development of advanced drug delivery platforms. Various strategies for subcellular targeting often involve modulating the characteristics of nanomaterials such as size, charge, and surface composition. Hence, nanomaterials can be designed to interact with specific internalization pathways within cells, thereby avoiding entrapment within lysosomes and effectively reaching their target organelles. Nanomaterials can be engineered for specific pathways that lead to their direct delivery to targeted organelles, overcoming lysosomal degradation. This may involve modifying the surface properties to facilitate interactions with cellular receptors or intracellular transport machinery that drive them toward their target organelles. [ 139 ]

Nanomaterials offer various routes of administration, with oral delivery being the most convenient route. However, achieving efficient oral delivery poses significant challenges because nanomaterials must traverse several barriers along the GI tract. The GI tract serves as the primary barrier to successful nanomaterial absorption, particularly during drug degradation. Enzymes such as proteolytic enzymes in lysosomes, brush border peptidases in villi, and pancreatic proteases in the duodenal region can degrade drugs carried by nanocarriers. [ 140 , 141 ] Additionally, the gut bacterial flora contributes to mucin production, further complicating its absorption. Epithelial cells lining the GI tract form a physiological barrier due to the presence of tight junctions. [ 142 ] These junctions restrict the paracellular transport of substances, including nanomaterials, across the epithelium. [ 139 ] Overcoming these barriers is crucial to ensure the successful absorption and bioavailability of orally administered nanomaterials. Strategies to enhance oral delivery efficiency involve optimizing nanomaterial properties and formulation techniques to improve the stability, mucoadhesion, and permeability across epithelial barriers. The ability to manipulate the size, charge, and surface composition of nanomaterials plays a pivotal role in determining the cellular internalization pathways. Nanomaterials can effectively prevent lysosomal degradation and interact with specific organelles by adjusting these properties. This capability has spurred the development of innovative platforms aimed at enhancing the bioavailability of nanomaterials and optimizing their therapeutic efficacy. [ 143 , 144 , 145 ]

Several methods have been used to invade cells using nanocarriers. One strategy is to outfit nanocarriers with membrane‐lysing agents such as fusogenic lipids or cell‐penetrating peptides, which perforate the cell membrane and permit direct access to the cytosol. [ 146 , 147 ] Although this approach provides effective intracellular administration, intracellular component permeability increases the risk of cytotoxicity and immunogenicity. Alternatively, endocytosis, a basic cellular mechanism that carries molecules from the extracellular environment into cells, allows nanocarriers to enter the cells. [ 147 , 148 ]

Targeting lysosomes with NPs is a promising strategy for enhancing the efficacy of cancer therapy while minimizing systemic toxicity. Lysosomes play a crucial role in the maintenance of cellular homeostasis and are integral to cellular waste management and recycling. Lysosomal function dysregulation has been implicated in various diseases, including cancer, making it an attractive target for therapeutic intervention. NPs offer an ideal platform for lysosomal targeting because of their unique physicochemical properties. Their small size, large surface area, and tunable surface chemistry enable efficient cellular uptake and intracellular trafficking. By engineering NPs to respond to lysosomal cues, such as low pH, drug release can be triggered selectively within lysosomes, enhancing therapeutic efficacy while reducing systemic toxicity. One strategy involves the incorporation of pH‐responsive moieties into NP formulations. When exposed to the acidic environment of lysosomes, these NPs undergo structural changes, leading to payload release. This pH‐triggered release mechanism ensures precise drug delivery to the lysosomes, where therapeutic agents can exert their effects more effectively. Using fluorescent BODIPY dyes for pH sensitivity, NPs can be conjugated to facilitate the real‐time monitoring of lysosomal targeting and drug release. By incorporating BODIPY dyes into NP formulations, researchers can track the intracellular fate of the NPs and validate lysosomal accumulation. [ 149 , 150 , 151 , 152 ] In cancer therapy, lysosomal targeting using nanocarriers is promising for acid‐activated tumor photodynamic therapy (PDT) and photoacoustic imaging. PDT involves the administration of photosensitizing agents that generate reactive oxygen species upon exposure to light, leading to localized cell death. By delivering photosensitizers specifically to lysosomes, nanocarriers can enhance the selectivity and efficacy of PDT against cancer cells, while minimizing damage to healthy tissues. [ 153 , 154 , 155 ]

Targeting the Golgi apparatus, a pivotal organelle in cellular trafficking and processing, is a promising strategy for therapeutic intervention and bioimaging. [ 156 , 157 ] Various nanocarriers have been engineered to precisely target the Golgi apparatus, each with a distinct targeting approach and carrying agent tailored for specific applications. Pdots, characterized by their exceptional optical properties, have emerged as valuable tools for long‐term near‐infrared fluorescent bioimaging. By incorporating trans‐Golgi network peptides into polymer dot formulations, these nanocarriers can actively target the Golgi apparatus. This targeted approach ensures the precise visualization of Golgi dynamics over extended periods, providing insights into intracellular processes with high spatiotemporal resolution. Polymer nanocarriers, however, offer a versatile platform for drug delivery, particularly in the context of treating tumor metastasis. Engineered to passively target the Golgi apparatus, polymer nanocarriers release therapeutic payloads upon accumulation in the tumor tissues. Celecoxib and brefeldin A, potent anticancer agents, are commonly encapsulated within polymer nanocarriers, effectively inhibiting tumor progression and metastasis while minimizing systemic side effects. Micelles are self‐assembling nanostructures composed of amphiphilic molecules that exhibit remarkable potential in antifibrotic therapies and the management of liver fibrosis. By actively targeting the Golgi apparatus through surface modification with chondroitin sulfate, micelles enable the precise delivery of therapeutic agents to cells, which are key players in fibrotic pathogenesis. Doxorubicin and retinoic acid encapsulated within micelles exert potent antifibrotic effects, mitigate fibrosis progression, and promote tissue regeneration. [ 158 ]

Polymer nanocarriers designed with triphenylphosphonium (TPP) for mitochondrial targeting effectively transport therapeutic drugs to mitochondria‐rich cells. The carrying agents used in this method are curcumin, 2,4‐dinitrophenol, lonidamine, and α‐tocopheryl succinate, each with unique therapeutic benefits. Curcumin, which is recognized for its strong antioxidant and antiinflammatory effects, is encapsulated in polymer nanocarriers to precisely target the mitochondria. [ 159 , 160 ] Using TPP's targeting capabilities of TPP, curcumin‐loaded NPs concentrate selectively within mitochondria‐rich cancer cells, exhibiting antiproliferative and proapoptotic effects. This focused method has the potential to improve the efficacy of curcumin‐based cancer treatments while reducing off‐target effects. Targeted delivery of these engineered nanoagents to mitochondria has the potential to treat mitochondrial dysfunction, which is associated with Alzheimer's disease. Indeed, mitochondria‐targeted therapy administered using polymer nanocarriers may reduce oxidative stress, alleviate neuronal damage, and improve cognitive performance in patients. [ 161 , 162 , 163 ]

The delivery of anticancer drugs to cancer cell nuclei using polymer nanocarriers is a promising strategy for improving cancer treatment outcomes. The targeting approach involves the utilization of fluorescein‐labeled nanocarriers with specific morphologies to ensure effective delivery to the nuclei. The carrying agent encapsulated within these nanocarriers is doxorubicin, a potent anticancer drug, which was encapsulated in these nanocarriers. By delivering doxorubicin directly to the nuclei of cancer cells, this approach enhances the effectiveness of the drug in inhibiting tumor growth and promoting cancer cell death. However, the morphology of nanocarriers can be optimized to enhance the nuclear targeting efficiency and ensure maximum therapeutic benefit. [ 148 , 164 , 165 ]

Tumor Microenvironment (TME) Barrier and Precise Drug Delivery

TMEs pose numerous obstacles to the effective delivery of therapeutic agents, thereby impeding treatment efficacy. The rapid tumor cell proliferation outpaces the capacity of neighboring blood vessels to supply oxygen and nutrients, resulting in a shortage of oxygen, known as hypoxia. Hypoxia triggers a cellular response primarily mediated by hypoxia‐inducible factors (HIF), including HIF1, HIF2, and HIF3. [ 166 , 167 ] These transcription factors regulate genes involved in various cellular processes such as glucose biosynthesis, angiogenesis, cell proliferation, migration, and immune response. In response to hypoxia, tumor cells undergo metabolic reprogramming, shifting from oxidative phosphorylation to aerobic glycolysis, a phenomenon known as the Warburg effect. [ 168 ] Despite the presence of oxygen, this metabolic switch leads to increased lactate secretion into the extracellular environment, thereby contributing to acidification. The heightened proliferation and glycolytic metabolism of tumor cells result in reactive oxygen species (ROS) generation, which damages cellular components, including DNA, leading to genomic instability. Additionally, ROS stimulate antioxidant responses in tumor cells, further complicating the TME and influencing tumor progression. Immune cells within the TME exhibit contrasting functions in tumor growth. [ 169 , 170 ] While B and regulatory T cells contribute to an immunosuppressive microenvironment, natural killer cells and natural killer T cells stimulate antitumor immunity. However, the increased expression of granulocyte‐macrophage colony‐stimulating factor and vascular endothelial growth factor (VEGF) leads to myeloid‐derived suppressive cell formation in the bone marrow, which inhibits cytotoxic T cells and NK cells, thus correlating with poor prognosis. [ 171 , 172 ] The interplay between different components of the TME, including enhanced desmoplasia and hypoxia, facilitates the epithelial‐to‐mesenchymal transition of tumor cells, leading to cancer stem cell formation and metastatic spread. Matrix metalloproteinases play a critical role in epithelial mesenchymal transition by degrading extracellular matrix (ECM) components and promoting cancer stem cell development. [ 173 ]

The TME orchestrates the formation of new blood vessels driven by the production of VEGF‐A by various TME components. VEGF‐A attaches to endothelial cells via the VEGF receptors, thereby stimulating angiogenesis. However, this process often results in abnormal blood vessels with damaged or undefined basal cells, leading to leaky vasculature and irregular structures surrounding the tumor. Dysfunctional blood vessels impair the delivery of nutrients and oxygen to the TME, exacerbating hypoxia and hindering the distribution of chemotherapeutic agents within the tumor. Moreover, the unstable composition of blood vessels contributes to the abnormal production of cytokines involved in the inflammatory and coagulation processes within the TME. Interestingly, the disorganized vasculature of the TME offers an opportunity for nanomedicines to selectively target tumor cells. Nanomedicines can exploit the leaky vasculature to preferentially accumulate within the tumor through a phenomenon known as the enhanced permeability and retention effect. Additionally, the TME promotes the lymphatic vessels development through the secretion of VEGF‐D and VEGF‐C by cancer, stromal, and immune cells, a process termed tumor‐associated lymphangiogenesis. However, lymphatic vessel development within the TME is associated with poor prognosis, as it facilitates metastatic spread to distant organs ( Figure 6 A ). [ 173 , 174 ]

The TME also exhibits significant heterogeneity in immune cell composition across different tumor types and stages of tumor development. This variability is driven by dynamic shifts and modifications occurring within the TME, resulting in the production of multiple activation factors such as chemokines and cytokines. TME involves the differentiation of monocytes into two major subsets of macrophages, namely M1‐type and M2‐type macrophages. Tumor‐associated macrophages (TAMs) typically exhibit the M2 phenotype and contribute to tumor progression by promoting metastasis, angiogenesis, and invasion. [ 175 , 176 ]

Nanotechnology holds great promise in transforming cancer therapeutics by facilitating precise drug delivery, minimizing side effects, and improving patient outcomes. Nanosized carriers offer a platform for improving anticancer drug pharmacokinetics by encapsulating them within or conjugating them to the surface of NPs. The selective delivery of nanotherapeutic platforms relies primarily on passive targeting mechanisms, such as enhanced permeability and retention effects. To date, in the TME, three strategies–normalization and promotion, permeabilization or disruption, and tumor‐associated platelet inhibition–have been developed to overcome the abnormal vasculature barriers and administration of nanoagents ( Figure 7 ) (Figure 6 Ba,b). [ 177 , 178 , 179 ]

TME defects, including compromised lymphatic drainage and increased permeability of the tumor vasculature, facilitate the accumulation of NPs, typically less than 200 nm in size, within the tumor tissue. Innovative NP‐based delivery systems are being explored to overcome physiological barriers and achieve targeted access to specific tumors ( Figure 8 ). Techniques such as mechanical particle deformation and synergistic approaches for delivering multiple chemotherapeutic agents such as paclitaxel and gemcitabine using mesoporous silica nanoconstructs have been investigated to enhance treatment efficacy. [ 180 ] In a study investigating nucleic acid‐based therapy, PEG‐modified NPs and transferrin‐modified NPs were assessed for their effectiveness. These NPs were loaded with nucleic acids and evaluated in human prostate cancer and chronic myelogenous leukemia cell lines. The findings revealed that targeted NPs exhibited enhanced efficiency compared to untargeted particles, particularly when transfected into K562 leukemia cells. [ 181 ]

Another strategy involves the utilization of NPs to deliver immunostimulatory or immunomodulatory molecules, either alone or in combination with traditional chemotherapy or radiotherapy. These NPs can also act as adjuvants to enhance the efficacy of other immunotherapies. Another promising application of nanocarriers in cancer immunotherapy is their ability to capture antigens released from tumors following radiotherapy. By encapsulating these antigens, nanocarriers can enhance immune recognition and responses to cancer cells. Nanocarrier‐based vaccines are also being developed to elicit robust T‐cell responses. These vaccines employ various strategies, including the codelivery of antigens and adjuvants, dendritic cell (DC) activation by multiple antigens, and sustained antigen release over time. Such vaccines have the potential to enhance the immune response of the body to cancer cells. Furthermore, nanotechnology enables in situ vaccination approaches where artificial antigenpresenting cells or immune depots are placed near tumors to stimulate local immune responses. [ 182 , 183 , 184 , 185 ] These strategies aim to harness the ability of the immune system to recognize and eliminate cancer cells, ultimately leading to improved treatment outcomes.

Epithelial Barrier and Formulation of Nanocarrier

The epithelial barrier plays a crucial role in controlling drug absorption and in preventing the invasion of pathogenic bacteria into the host. Comprising epithelial cells, tight junctions, and a mucus layer, this barrier regulates nutrient absorption and interactions between the luminal contents and the underlying immune system. Goblet cells produce mucus that shields epithelial cells from bacterial interactions and physical damage caused by ingested food. [ 186 ] Despite its vital role in intestinal protection, the mucus layer presents an initial challenge for nanocarriers. Many nanomaterials are trapped in the mucus gel layer, [ 187 ] which hinders their ability to reach the intestinal epithelial cell layer. Once a nanocarrier penetrates the mucus layer, the primary obstacle is to cross the epithelial cells. [ 188 , 189 , 190 ]

Nanocarriers must traverse the epithelial cell layer to overcome the intestinal barrier. The GI tract presents several barriers to drug absorption, including the gastric barrier in the stomach and mucus and epithelial barriers. Strategies such as decorating nanocarriers with PEG chains, combining anionic and cationic charges, and utilizing self‐nanoemulsifying DDSs have proven to be effective in penetrating the mucosal barrier. Another approach involves decorating NPs with proteolytic enzymes, such as papain, to cleave mucoglycoprotein substructures, which have been shown to increase mucosal penetration. [ 191 , 192 , 193 , 194 , 195 , 196 , 197 ] Many studies have reported endocytosis in human colorectal adenocarcinoma cells because the intestine represents the initial barrier to oral drug delivery via nanocarriers. Generally, positively charged NPs exhibit better uptake than negatively charged NPs, as demonstrated by 50 and 100 nm PS‐NP in Caco‐2 cells. [ 198 , 199 ] In contrast to epithelial cells, caveolae are the most prevalent endocytic structures in endothelial cells that line blood vessels. Consequently, numerous studies have examined caveolin‐mediated endocytosis of nanomaterials. For example, 20–100 nm BSA‐coated polymeric NPs in bovine lung microvascular endothelial cells are predominantly internalized through this pathway. [ 192 , 200 , 201 , 202 , 203 ]

Clinical Achievements of Nanocarriers‐Based DDSs

The nanopharmaceutical market has witnessed significant commercial success, with initial product offerings markedly enhancing the therapeutic effectiveness of numerous small‐molecule drugs. [ 204 , 205 , 206 ] According to BCC Research, the global pharmaceutical market was valued at USD 209 billion in 2014. However, the landscape has evolved, and the COVID‐19 pandemic has significantly impacted market dynamics. In 2022, the global nanopharmaceutical market size is estimated to be USD 35 330 million, reflecting the effects of the pandemic. Nevertheless, the market is forecasted to undergo substantial readjustment, reaching USD 73 550 million by 2028, with a CAGR of 13.0% during the review period. This revision considers economic changes caused by the health crisis. Specifically, liposomes, which account for a significant portion of the global nanopharmaceutical market in 2021, are projected to reach USD million by 2028, growing at a revised percentage CAGR post‐COVID‐19 period. Similarly, the Cancer and Tumor segments experienced an altered percentage CAGR throughout the forecast period. Geographically, the market is predominantly concentrated in the USA (35% of the global market share), Asia (25%), and Europe (25%). Globally, over 200 companies are actively developing nanopharmaceuticals, approximately three‐quarters of which are start‐ups or small and medium enterprises ( Table 4 ). This diversity of players underscores the dynamic and competitive nature of the nanopharmaceutical industry. [ 19 , 26 , 207 , 208 , 209 , 210 ]

The anticipated nanopharmaceutical market growth is driven by the emergence of a new generation of nanocarrier‐based systems. These advancements include the delivery of biotherapeutics, particularly nucleic acids, polymeric formulations, targeted nanocarriers, and metal‐based nanocarriers that act as therapeutic agents under external stimuli. Additionally, existing delivery technologies, such as nanocarrier‐based albumin‐bound technology, are being repurposed for other classes of drugs. For example, there is an ongoing investigation into the use of this technology for rapamycin delivery. Moreover, the development of nanocarrier‐based DDSs is becoming increasingly prevalent and is expected to substantially contribute to the growth of the nanopharmaceutical market.

The primary advantages of first‐generation nanopharmaceuticals over their parent drugs are twofold: 1) improvement of the pharmacokinetic profile, leading to reduced toxicity; and 2) enhancement of pharmaceutical efficacy or dosing through drug reformulation. [ 211 ] One notable example of a first‐generation nanopharmaceutical is Doxil, which became the first nanoscale drug carrier to receive FDA approval in the United States, just 5 years after its initial development. Clinical studies have demonstrated that Doxil exhibits superior therapeutic efficacy in treating ovarian cancers and AIDS‐related Kaposi's sarcoma compared to standard therapies. [ 212 , 213 , 214 , 215 ] It also demonstrated equivalent efficacy in treating multiple myeloma and metastatic breast cancer. However, despite its overall better tolerability, Doxil infusion has been associated with skin toxicity, specifically Palmar Plantar erythrodysesthesia or hand–foot syndrome. This adverse effect was attributed to the slow extravasation of PEGylated liposomes into the skin due to their prolonged circulation time. Following the approval of Doxil, several other liposomal and lipid‐based delivery systems have been developed and gained approval, including lipid nanocarriers and nanoemulsions. Moreover, the pharmaceutical industry has shifted its focus beyond small‐molecule compounds to the development and manufacture of various biotherapeutics, including recombinant proteins, monoclonal antibodies, antibody fragments, and nucleic acids.

Challenges Associated with Nanocarriers‐Based DDSs

Nanocarriers offer several benefits as DDSs, including precise drug delivery, surmounting biological barriers, and reducing adverse effects associated with traditional drug delivery methods. However, despite their potential advantages, NPs present certain obstacles and constraints, notably concerning their potential toxicity and intricate manufacturing processes. One notable concern arising from the increased use of NPs is the risk of nano‐toxicity. [ 216 , 217 , 218 ] Elevated intracellular ROS levels have been associated with the accumulation of diverse nanocarriers, resulting in oxidative stress and adverse effects on various organ systems, including the respiratory, skin, liver, kidney, reproductive, embryonic, central nervous, and immune systems. These adverse effects are frequently attributed to factors such as nanocarrier dimensions, morphology, surface characteristics, method of administration, and interactions with biological barriers.

To overcome these challenges and enhance the performance of nanocarrier‐based DDSs, numerous areas of research and development warrant prioritization. Enhancing nanocarrier stability in biological settings is crucial for ensuring effective drug delivery. Strategies to bolster stability may involve surface modifications, formulation enhancements, and utilization of stabilizing agents. Additionally, achieving an efficient distribution of bioactive compounds to target tissues or cells is essential for optimizing therapeutic outcomes. Research endeavors should concentrate on enhancing drug absorption capabilities, attaining site‐specific targeting, and augmenting drug transport to desired locations within the body. [ 219 , 220 ] The development of nanocarrier systems capable of controlling drug release kinetics can aid in optimizing drug delivery and minimizing off‐target effects. This may entail the design of stimuli‐responsive nanocarriers or the incorporation of release‐modulating components. Overcoming biological barriers, such as the BBB or mucosal barrier, is pivotal for successful drug delivery. Strategies aimed at enhancing NP penetration and retention at target sites are critical for enhancing therapeutic outcomes.

Implementing advanced safety measures for nanocarrier characterization, identification, and toxicity assessment is indispensable for ensuring patient safety. This may necessitate the establishment of standardized protocols, robust quality control systems, and a comprehensive preclinical evaluation of nanocarrier formulations. The commercial development of nanocarrier‐based DDSs presents distinctive challenges in terms of manufacturing, characterization, and regulatory approval. Scaling up nanocarrier production to meet clinical demands while upholding batch‐to‐batch reproducibility and quality control standards necessitates meticulous optimization and coordination among the research, development, and manufacturing teams. Furthermore, ensuring adherence to regulatory requirements and addressing safety concerns are pivotal steps in the translation of nanocarrier‐based DDSs from laboratory to clinical settings.

Future Prospectives of Artificial Intelligence in Biomedicine Research

The integration of AI systems has a profound impact on medicine and medical science. This impact includes the use of machine learning (ML), deep learning, and quantitative structure–activity relationship modeling in nanoscience, providing a comprehensive predictive assessment of nanomaterials, chemicals, and toxicological effects on biological systems. [ 221 , 222 , 223 ] These technologies can analyze complex medical data, such as imaging scans, genetic sequences, and patient records, to assist clinicians in making accurate diagnoses, predicting treatment outcomes, and identifying optimal treatment strategies. Clinical decision‐support tools enable clinicians to swiftly provide access to highly relevant information, enabling informed decisions regarding patient treatment, medications, and other care needs. Additionally, AI tools analyze various medical images, such as CT scans, X‐rays, and magnetic resonance imaging, aiding radiologists in achieving precise diagnoses by detecting lesions or other markers. [ 224 , 225 , 226 ] AI is at the forefront of driving biomedical research by enabling data‐driven insights, expediting the drug discovery process ( Table 5 ), and fostering personalized healthcare approaches. Its applications span various domains, including clinical decision support and medical image analysis, in healthcare settings.

Convergence of AI with Nanoscience and Modeling of Nanocarriers for Drug Delivery

AI has emerged as a cornerstone in the field of drug delivery modeling, offering profound insights into biological systems and revolutionizing the optimization of nanosystem designs [ 227 , 228 ] ( Figure 9 A–J ). In the context of drug delivery, the intricacies of the human body are simplified into distinct compartments delineated by biological barriers. These barriers, which are permeable through active or passive mechanisms, are critical considerations in drug transport. Passive diffusion, governed by the molecular properties of drugs, undergoes dynamic alterations upon exposure to physiological environments, enabling the predictive modeling of drug distribution complexes. In contrast, active diffusion involves energy‐activated transporter systems to facilitate drug transport across biological membranes. This intricate interplay between membrane transporters and drug molecules lends itself to computational modeling, which enables the analysis of various parameters.

Artificial neural networks (ANNs) have been harnessed to unravel the quantitative relationships between different formulations, processing variables, and the ensuing in vitro and in vivo characteristics. In nanotechnology, ANNs have been employed to characterize the structural properties of nanomaterials; estimate the effective dielectric constant of thin films; model the nanoprecipitation of insoluble drugs such as prednisolone; and characterize physiochemical properties such as water uptake, viscosity, and glass transition state of amorphous polymers. [ 229 , 230 ] Through meticulous modeling, predictive algorithms are formulated, enabling the accurate estimation of formulation properties based on input variables, such as material attributes and process parameters. This predictive capability facilitates the optimization of formulation properties tailored for specific applications, ensuring the efficacy and precision of drug delivery. Moreover, ANNs are invaluable tools for predicting the fundamental properties of polymers, including moisture content, viscosity, glass transition temperatures, and water‐uptake profiles. Such predictive models offer invaluable insights during the preformulation stage, guiding the development process toward optimal outcomes. The integration of AI modeling extends beyond formulation optimization to encompass the diverse facets of drug delivery. AI‐driven methodologies streamline various aspects of DDS development by predicting dissolution profiles to evaluate the transportability of drugs and identify suitable polymer composites. [ 231 ]

Accurately modeling nanoscale circumstances is a fundamental challenge in nanotechnology. Nanoscale data is typically interpreted through numerical simulations, as real optical images cannot be obtained at such high resolutions. [ 232 , 233 ] However, these simulations often involve complex processes that require the integration of multiple parameters, which can make the modeling process overwhelming. AI can be highly beneficial in this context, as it simplifies the modeling process, enabling more effective and straightforward interpretation of nanoscale data. Using sophisticated algorithms, AI can generate more accurate simulations, reduce the need for manual parameter adjustments, and enhance our overall understanding of nanoscale images. [ 234 , 235 ]

The interaction of formulation, process factors, and controlled release in DDSs is inherently complex and nonlinear, making optimization challenging for achieving successful therapeutic effects. Neural network designs are particularly well‐suited for addressing these issues. These architectures consist of multiple interconnected layers, each containing nodes that enable prediction, classification, or recognition based on input data. AI approaches have been developed to predict the performance of drug combinations by analyzing pharmacological synergies, leading to more precise and effective therapies. AI‐based optimization also has significant applications in combination drug delivery, where different types of NPs are employed to enhance drug localization at tumor sites, resulting in improved treatment outcomes [ 228 , 236 ] ( Figure 10 ).

Furthermore, by integrating diverse data sources, AI has shown great potential in understanding complex biological interactions, such as those involving cellular membranes. Inputs like drug interactions, phenotypic data, chemical interactions, and genomic information are critical for optimizing drug delivery and enhancing pharmacokinetic analyses. AI can be leveraged to make more accurate predictions and optimize nanocarrier delivery systems, leading to better‐targeted therapies and improved patient outcomes ( Table 6 ).

Conclusion and Future Perspectives

In conclusion, nanocarrier drugs have revolutionized healthcare and pharmaceutical systems, offering novel solutions to the longstanding challenges in drug delivery. The integration of advanced nanotechnologies into drug delivery highlights their profound impact on modern medicine. This review explores a multitude of nanocarrier designs specifically tailored for therapeutic delivery, intending to overcome the diverse biological barriers encountered in different patient populations and diseases. Targeted delivery, characterized by the precise placement of medicines in the tissue of interest, is a pivotal drug delivery aspect. Mechanisms focused on medication targeting should ideally be capable of regulating the fate of the drugs upon their entry into the body. Nanocarriers, with their unique properties, have shown remarkable potential in facilitating enhanced delivery of poorly soluble drugs, thereby reshaping the therapeutic landscape for various hard‐to‐treat diseases.

The ability of nanocarriers to improve drug delivery efficiency has already begun to have a profound impact on the treatment of various ailments. By overcoming barriers, such as limited solubility, rapid clearance, and off‐target effects, nanocarrier‐based therapies hold promise for significantly improving the quality of life of a broad spectrum of patients. Some studies have discussed the multiple factors involved in the generation of nano–bio interfaces. These factors, such as slight differences in size, can modify the surface structure and functionality of the nanomaterials, leading to the reconformation of biomolecules. However, the development of a nano–bio interface can also be advantageous, as it can reduce the biotoxicity of nanomaterials and increase their suitability for biological applications. [ 237 ] We anticipate that additional advances in DDSs and nanotechnology will further enhance and improve therapeutic interventions. [ 208 ] These advancements have the potential to not only enhance the efficacy and safety of treatments but also enable more precise targeting of specific tissues or cells, minimize side effects, and optimize therapeutic outcomes.

The widespread adoption of nanocarrier drugs has revolutionized clinical practice and patient care. Maintaining ethical standards in nanocarrier research, especially when involving human or animal studies, is essential for ensuring the safety, efficacy, and social acceptability of nanotechnology in medicine. Risk–benefit analysis is a critical component of ethical considerations, providing a structured evaluation of the potential benefits of the research against the risks to participants or test subjects. Regulatory compliance is another vital aspect, with ethical reports often including detailed assessments of how the research aligns with regulatory guidelines. Ethical boards, such as Institutional Review Boards (IRBs) for human studies or Institutional Animal Care and Use Committees (IACUCs) for animal studies, play a crucial role by providing an independent evaluation of the research's ethical soundness.

As advancements in nanotechnology continue, the convergence of AI with nanotechnology holds promise for further refinement of targeted delivery mechanisms. The synergy between AI and nanotechnology has the potential to catalyze the development of highly personalized and precise DDSs. In this envisioned healthcare landscape, tailored treatments will become the norm, with therapies precisely optimized to target specific tissues or cells, while minimizing off‐target effects. By harnessing the power of AI‐driven algorithms to analyze vast amounts of patient data, healthcare providers can tailor drug delivery strategies for individual patient profiles, thereby ensuring the highest level of therapeutic efficacy and safety.

Ultimately, the ongoing development and refinement of nanocarrier‐based therapies represents a paradigm shift in medicine, offering unprecedented opportunities to improve patient health and well‐being on a global scale. Given the transformative potential of nanotechnology and AI, we can use them in a new precision medicine era, where each patient receives personalized treatments tailored to their unique physiological characteristics and medical needs. By leveraging the capabilities of nanocarriers and scientific progress, we can look forward to a future in which personalized medicine becomes increasingly tailored and effective, ultimately leading to improved patient care and outcomes.

Conflict of Interest

The authors declare no conflict of interest.

Author Contributions

Minhye Kim wrote the partial script. Myeongyeon Shin and Yaping Zhao took care of analysis and Investigation. Mrinmoy Ghosh took care of writing, original draft, review, and editing the manuscript. Young‐Ok Son took care of supervision, dunding acquisition, and project administration. All authors were involved in writing the manuscript and provided their final approval for the submitted and published versions.

Acknowledgements

The figures were created using BioRender.com and were modified accordingly. The authors would like to thank Editage (www.editage.co.kr) for English language editing. This work was supported by the National Research Foundation of Korea (NRF), funded by the Korean government (MSIT; grant nos. 2020R1A2C2004128 and RS‐2023‐00208776), the Basic Science Research Program of the Research Institute for Basic Sciences (RIBS) of the Jeju National University through the NRF, funded by the Ministry of Education (grant no. 2019R1A6A1A10072987), and a Korea Basic Science Institute (National Research Facilities and Equipment Centre) grant funded by the Ministry of Education (grant no. 2020R1A6C101A188). This research was also partly supported by the Brain Pool Program, funded by the Ministry of Science and ICT through the NRF (grant no. 2022H1D3A2A02053110), “Regional Innovation Strategy (RIS)” through the National Research Foundation of Korea(NRF) funded by the Ministry of Education(MOE)(2023RIS‐009), and the National University Development Project, 2024.

Biographies

Minhye Kim is currently pursuing her M.S. in the interdisciplinary graduate program in advanced convergence technology and science at Jeju National University, South Korea, under the mentorship of Professor Young‐Ok Son. She holds a B.S. in animal biotechnology from the same university. Her research focuses on the role of PARP‐1 in cartilage degeneration and osteoarthritis pathogenesis and osteoarthritis prevention using single compounds from natural resources.

Myeongyeon Shin is currently pursuing her integration of M.S. and Ph.D. courses in animal biotechnology at Jeju National University, South Korea, under the mentorship of Professor Young‐Ok Son. She holds a B.S. in animal biotechnology from the same institution. Her research interests focus on the Chil1 mechanisms of cartilage degeneration and osteoarthritis and osteoarthritis prevention using single compounds from natural resources.

Yaping Zhao , a tenured professor at Shanghai Jiao Tong University's School of Chemistry and Chemical Engineering, serves as an associate editor of The Journal of Supercritical Fluids. He earned his Ph.D. from Jiangsu University in 1997 and completed postdoctoral research at Jiangnan University (1997–1999). Dr. Zhao joined Shanghai Jiao Tong University as an associate professor in 1999, becoming a full professor in 2002. He was a visiting scholar at Chunbuk National University (2005–2006) and Stanford University (2009–2010). His research focuses on advanced functional nanomaterials, and he has published over 130 peer‐reviewed papers.

Mrinmoy Ghosh is an associate professor in the Department of Animal Biotechnology at Jeju National University, South Korea. Holding a Ph.D. in molecular biology, his research focuses on nanocarrier‐mediated microRNA therapies for arthritis. Internationally recognized, he received the prestigious Brain Pool Fellowship (2022–2024). Dr. Ghosh is also an active contributor to the scientific community, serving on editorial boards and grant review panels, and is renowned for his innovative work in biotechnology, inspiring peers and future scientists alike.

Young‐Ok Son , Ph.D., is an associate professor in the Department of Animal Biotechnology at Jeju National University, South Korea, and an adjunct professor in the interdisciplinary graduate program in Advanced Convergence Technology and Science. He leads the BK21 FOUR Program for Biohealth/Innovative Drug Development using Subtropical Bio‐Resources. With a Ph.D. in cell biology from Chonbuk National University, his research focuses on cartilage degeneration, osteoarthritis pathogenesis, and therapeutic strategies. He is recognized with awards like Best Professor for Research (2023) and actively contributes to his field through extensive editorial and grant review work.

Contributor Information

Mrinmoy Ghosh, Email: mringhs2010@jejunu.ac.kr.

Young‐Ok Son, Email: sounagi@jejunu.ac.kr.

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