Zwitterion-Based Polymeric Carriers for Efficient Drug Delivery across Biological Barriers

Abstract

Polymeric carriers, by virtue of their tunable physicochemical properties, serve as critical platforms for drug delivery. To enhance therapeutic efficacy, considerable effort has been devoted to functionalizing polymeric carriers and exploring alternative routes of administration. However, regardless of the administration modality, polymeric carriers must overcome multiple physiological barriers during delivery. In this context, zwitterionic-rich polymeric carriers exhibit superior penetration across physiological barriers, attributable to their remarkable hydration capacity and resistance to protein adsorption. Understanding how the zwitterion structure governs barrier penetration is critical for designing drug delivery systems with enhanced tissue targeting. This review summarizes the design strategies of zwitterion-based polymeric carriers, focusing on their structure–activity relationships and mechanisms for overcoming specific physiological barriers via different administration routes. Finally, we provide perspectives on harnessing artificial intelligence for the intelligent design of zwitterion-based polymeric carriers toward their accelerated clinical translation.

1. Introduction

The optimization of drug delivery strategies aims to achieve targeted delivery to specific sites in the body (e.g., tumors), minimize off-target distribution, and reduce side effects. − Several platforms, such as viral vectors, molecular conjugates, antibody-drug conjugates, and nanoparticles, have been incorporated into clinical products to enhance targeting. , However, various biological barriersincluding mucus, epithelial cell layer, and endocytic pathwayscan significantly impede this process. − Zwitterion-based polymeric carriers, owing to their unique hydration and dynamic charge-regulation mechanisms, are increasingly recognized as a promising platform for overcoming biological barriers to enhance drug delivery and therapeutic efficacy. −

Effective drug delivery carriers must resist degradation and clearance while exhibiting minimal immunogenicity. Zwitterionic polymers satisfy these criteria through intrinsic charge neutrality and minimal dipole moments, which generate robust hydration via ionic solvation. This hydration layer outperforms poly­(ethylene glycol) (PEG)-based materials reliant on hydrogen bonding, conferring exceptional antifouling properties and low immunogenicity. ,, Unlike hydrophobic or cationic modifications that enhance membrane affinity, zwitterionic polymers leverage their unique electroneutral and ultrahydrophilic surfaces to suppress nonspecific protein adsorption and attenuate immune clearance. Maintaining charge neutrality at physiological pH avoids electrostatic repulsion with anionic membranes, thereby improving penetration efficiency and overcoming the intrinsic permeability limitations of anionic systems (Table ). , Notably, certain ZIPs exploit structural features for phospholipid interaction, endowing them with distinctive cell-membrane penetration capabilities. ,,

1. Biomaterials for Physiological Barrier Enhancement and Drug Delivery.

materials	surface charge	hydration mechanism	interaction with physiological barriers	biocompatibility
PEGylated Polymers	electroneutral (amphiphilic)	H-bonding (weaker, less stable layer)	steric hindrance (delayed cellular uptake)	high (immunogenicity)
cationic polymers	strongly positive (easy toxicity induction)	weak hydration (electrostatic-dependent)	strong electrostatic binding (membrane damage, difficult desorption)	low (cytotoxicity risk)
anionic polymers	strongly negative (cell membrane repulsion)	high affinity (electrostatically labile)	strong electrostatic repulsion (low penetration efficiency)	moderate (immune response risk)
zwitterionic polymers	overall neutral (antifouling)	ionic solvation (strongly bound hydration layer)	dynamic and reversible (promoting penetration)	high (biomimetic)

Catalyzed by Wilhelm et al.’s landmark meta-analysis reporting a sobering 0.7% median delivery efficiency of nanomaterials to solid tumors, current research focuses on sequentially navigating nanoparticles: from systemic administration to target tissues, specific cell types, and ultimately subcellular compartments. , Various administration routes facilitate nanoparticle access to tumors or inflammatory sites. Systemic delivery via oral or intravenous pathways offers convenience and broad distribution; more localized approaches, including inhalation, subcutaneous, intratumoral, and in situ implantation, enable direct tissue interaction while circumventing vascular transport and reducing systemic exposure. However, each route presents distinct transport barriers that effective delivery systems must overcome. ,

In the context of drug delivery, the endothelial barrier constitutes a critical obstacle, representing a fundamental component of physiological barriers in numerous tissues. Upon intravenous administration, the vascular endothelium impedes nanoparticle translocation, while endothelial cells within target tissues further restrict their uptake. ,,− Furthermore, the blood–brain barrier (BBB) represents a particularly specialized case. Unlike peripheral endothelium, brain endothelial cells lack the transcellular pores that normally facilitate rapid molecular exchange. , The BBB’s unique architecture is essential for protecting the brain from blood–borne toxins. However, it also blocks the passage of most small-molecule and macromolecular therapeutics (e.g., peptides, proteins, and nucleic acids), severely limiting treatment options for central nervous system disorders such as neurodegenerative diseases, brain tumors, cerebral infections, and stroke. ,−

The mucus barrier represents the foremost physiological impediment in most mucosal drug delivery systems (e.g., oral, pulmonary, and intrarectal administration routes). , Beyond serving as a physical barrier, the mucosa can enzymatically degrade therapeutics, rapidly clear substances, and present an immunosuppressive microenvironment, along with variable pH and diverse microbiota. Ideal mucosal drug delivery systems require multistage precise regulation: maintaining structural integrity prior to target site arrival, resisting mucociliary clearance while efficiently penetrating mucus layers, and ultimately achieving robust target cell uptake for desired therapeutic outcomes. ,,, In oral drug delivery systems, the gastric acid barrier and intestinal mucosal barrier (comprising the mucus barrier and the epithelial cell barrier) have become the key determinants of bioavailability. Moreover, drugs absorbed via the intestinal tract are subject to hepatic first-pass metabolism, further attenuating systemic drug exposure. To circumvent the first-pass effect, pulmonary inhalation represents a non-invasive strategy that facilitates direct alveolar absorption into systemic circulation or mediates rapid local therapeutic action. , However, pulmonary drug delivery also faces multiple physiological barriers. Beyond innate mucociliary clearance, inhaled therapeutics are susceptible to alveolar macrophage-mediated phagocytosis and complex epithelial interactions, which collectively precipitate premature clearance or degradation before reaching target sites.

ZIPs have emerged as promising candidates in drug delivery systems, demonstrating significant potential in overcoming multiple physiological barriers through their unique anti-fouling and hydration properties. ,, Understanding the interaction mechanisms of ZIP-based systems with biological barriers is crucial for better designing efficient tissue-penetrating nanocarriers. This review examines the biological barriers across diverse administration routes discussed earlier, systematically summarizes how zwitterion-modified systems leverage their chemical and structural functionalities to cross these barriers, and analyzes advanced technological strategies to enhance the transport (Figure ). Finally, integrating artificial intelligence methodologies, we provide perspectives on future development of ZIP-based delivery systems capable of efficiently transporting across biological barriers.

1.

Zwitterionic polymer-based nanocarriers navigate distinct physiological barriers dictated by the specific administration route.

2. Biological Barriers to Intravenous Administration

Intravenous injection is recognized as the route of administration with the highest bioavailability. This is because it introduces drugs directly into the systemic circulation, achieving a bioavailability of 100% by completely avoiding absorption processes and first-pass metabolism. , Following intravenous injection, the effective delivery of drug delivery systems is confronted with multiple physiological barriers. The primary challenge lies in evading non-specific adsorption by plasma proteins and immune clearance during systemic circulation. Subsequently, the drug delivery systems must traverse the endothelial barrier, where the integrity of tight junctions between endothelial cells and transmembrane pH gradients collectively restricts the transport efficiency via both paracellular and transcellular pathways. Ultimately, within target tissues (e.g., solid tumors), the dense extracellular matrix and abnormally elevated interstitial fluid pressure constitute critical physical and biological barriers to deep penetration. ,, To overcome these sequential barriers, the application of zwitterionic materials has demonstrated remarkable advantages, particularly in prolonging the in vivo circulation time of nanocarriers, owing to their exceptional resistance to nonspecific protein adsorption. However, fully exploiting the transport disparities between the vascular lumen and lesion tissues to achieve efficient accumulation and precise targeting at pathological sites remains a key scientific challenge.

2.1. Intravenous Zwitterionic Nanomedicines Target Tumor Tissue

Intravenous administration is the most common route for cancer nanomedicine as it enables a rapid therapeutic response. , Clinical evidence demonstrates that tumor cells are encompassed by a complex physical-biological barrier consisting of immunosuppressive cells (e.g., TAMs and MDSCs), cancer-associated fibroblasts (CAFs), and dense extracellular matrix (ECM). , To overcome the limitations imposed by these barriers on drug delivery, the research paradigm in cancer nanomedicine is progressively shifting from passive reliance on the enhanced permeability and retention (EPR) effect toward active targeting design. For example, the albumin-mimicking nanodrug could be designed, consisting of dipalmitoyl-phosphatidylcholine (DPPC), a component of zwitterionic poly­(glutamatyl lysine-co-cysteine) peptides scaffold. This biomimetic approach protected the cargo against degradation and enhanced pH-triggered tumor targeting via prolonging circulation time. Furthermore, the nanodrugs demonstrated excellent MCF-7 cell uptake at tumor microenvironmental pH 6.7 in both ICR mice and nude mice bearing subcutaneous MCF-7 human breast tumors treated with DOX. Nishiyama and colleagues previously developed a novel polyzwitterion, ethylenediamine (EDA)-based-poly-glutamide (PGlu­(DET-Car)). Functionalization of nanomedicines with PGlu­(DET-Car) enabled pH-responsive behavior within the narrow pH window of the tumor microenvironment (Figure a,b). The ethylenediamine moiety in the carboxybetaine enabled stepwise protonation and initiated the diprotonation process around tumorous pH (6.5). The net charge of the developed polyzwitterion (PGlu­(DET-Car)) was thus neutral at pH 7.4 for antifouling but was cationic at pH 6.5 for interaction with anionic constituents. This pH-triggered charge reversal resulted in enhanced tumor accumulation and efficient endosome escape compared with conventional PEG-coated systems. Additionally, they synthesized a series of ethylenediamine-based polyzwitterions bearing carboxy/sulfonic groups and ethylene/propylene/butylene spacers as candidate surface coatings for nanomedicines. These polymers enabled sensitive detection of tumor acidic environments (pH = 6.5–5.5), and the investigations revealed that the C/A value and the interplay between anionic groups and spacer length were critical parameters determining antifouling efficacy.

2.

(a) Schematic illustration of pH-triggered PGlu­(DET-Car) property switching. (b) Chemical structures and pH-dependent side-chain protonation of PGBs (pH 6.5–7.4). Reproduced from ref . Copyright 2018 John Wiley and Sons. (c) Molecular structures of the OPDEA-SN38 and OPDEA-PSN38. (d) The schematic of transcytosis-based active tumor penetration. (e) In vivo photoacoustic images showing tumor-targeted accumulation of OPDEA-Cy5.5PSN38 micelles. Scale bars, 1.0 mm. (f) Ex vivo fluorescence imaging of hypoxia-targeted accumulation of intravenously administered OPDEA-RhoBPSN38. n = 3 biological replicates. Scale bars, 100 μm. Reproduced from ref . Copyright 2021 Springer Nature.

In another example, Shen et al. designed and synthesized Poly­[2-(N-oxide-N,N-diethylamino) ethyl methacrylate] (OPDEA), a ZIP featuring tertiary amine N-oxide structures that resisted protein adsorption while reversibly adsorbing to cell membranes, thereby achieving prolonged circulation and tumor accumulation via “stealth” behavior in the bloodstream. On the other hand, its rapid internalization by tumor vascular endothelial cells and tumor cells triggered active transcytosis, thereby enabling efficient tumor vascular extravasation and active tumor penetration. Building on this, they fabricated tumor-penetrating nanomicelles featuring an OPDEA hydrophilic corona and an SN38 prodrug polymer core. After intravenous injection via the tail vein, these micelles reversibly adsorbed onto red blood cells while evading plasma protein adsorption, achieving prolonged blood circulation. Upon reaching the tumor site, it weakly adsorbed onto tumor vascular endothelial cells to trigger transcytosis, rapidly extravasating into tumor tissue, and then achieved efficient penetration via tumor cell-mediated transcytosis, infiltrating avascular, hypoxic, and necrotic regions to deliver the drug to all cells, ultimately eradicating the entire tumor cell population (Figure c,f). Continuing this work, another study by Shen et al. further investigated how the N-alkyl chain length of zwitterionic poly­(sulfobetaine) affected long blood circulation and fast cellular internalization of efficient tumor-targeted drug delivery carriers. As the affinity of micelles for cell membrane increased with respect to alkyl chain length, their study showed that PSB4 (with a butyl alkyl chain) was precisely at an optimal equilibrium point, where it could effectively bind to the cell membrane to drive transcytosis without being rapidly cleared due to excessive protein adsorption. This single structure addresses multiple complex issues by merely modulating the alkyl chain length, endowing the carrier with key capabilities, such as long circulation, strong accumulation, deep penetration, and high uptake.

2.2. Intravenous Zwitterionic Nanomedicines Target the Central Nervous System

Upon intravenous administration, the BBB constitutes a uniquely formidable and mechanistically distinct impediment that fundamentally governs cerebral delivery efficiency to the central nervous system (CNS). − The BBB comprises a physical barrier of tight junctions between brain microvascular endothelial cells, a biochemical barrier mediated by efflux transporters (e.g., P-glycoprotein), and a cellular barrier reinforced by astrocytic end-feet and pericytes. ,, This multi-layered defense network severely restricts therapeutic efficacy for CNS disorders, including brain tumors and neurodegenerative diseases. ,, As mentioned earlier, relying on charge balance, a strong hydration layer, and excellent biocompatibility, zwitterionic materials have unique advantages in resisting non-specific protein adsorption and prolonging in vivo circulation time. Critically, certain zwitterionic materials can actively engage with specific transporters or receptors on the BBB. This interaction facilitates receptor-mediated transcytosis, thereby overcoming the fundamental limitation of drug delivery imposed by the BBB. − Notably, Yunfeng Lu and colleagues developed the 2-methacryloyloxyethyl phosphorylcholine (MPC)-based nano-delivery system wherein the choline moieties mimic acetylcholine to selectively engage overexpressed nicotinic acetylcholine receptors (nAChRs) and choline transporters (ChTs) on brain microvascular endothelial cells, thereby enabling receptor-mediated transcytosis across the BBB. ,, Leveraging the unique capability of zwitterionic MPC-based platforms to traverse the blood–brain barrier, this delivery strategy has shown great potential and is being actively investigated for a broad spectrum of brain disorders, extending beyond its initial applications.

For instance, Wu et al. demonstrated that MPC nanocapsules traversed the BBB via ChT/nAChR-mediated active transcytosis, enabling the effective delivery of therapeutic proteins to the CNS, as demonstrated in mice and non-human primates (Figure a). Importantly, intravenous administration in rhesus monkeys confirmed the excellent biocompatibility of this platform, with liver and renal function markers and complete blood count parameters all remaining within normal ranges. Li et al. pioneered a “motion-enhanced penetration” strategy by integrating zwitterionic coatings with nanomotor technology. Their drug-loaded nanomotors achieved 4.5-fold higher accumulation at spinal cord injury sites compared to conventional nanodrugs via magnetically driven self-propulsion. The zwitterionic surface endowed the system with excellent biocompatibility and enhanced its ability to penetrate the blood-spinal cord barrier (BSCB). This treatment effectively reduced the extent of the lesion’s interstitial space from 1500 to 800 μm. This work establishes a novel therapeutic modality for neural injuries, including spinal cord injury.

3.

(a) Schematic illustration of nAChR/ChT-mediated BBB penetration by choline and acetylcholine analogues-rich protein nanocapsules. Reproduced from ref . Copyright 2019 John Wiley and Sons. (b) Schematic illustration of pH-responsive diblock PCL-PSDMA micelles undergoing charge conversion. Reproduced from ref . Copyright 2025 American Chemical Society.

On the other hand, this strategy has been extended to CNS cancer models, the work of Han et al. demonstrating that encapsulation of rituximab within the crosslinked ZIP layer achieved a 10-fold increase in CNS antibody concentrations, sustained therapeutic levels over 4 weeks, and prolonged median survival by 22.7%. In addition, Zheng et al. showed that ZIP PMPC-modified immunomodulatory nanoparticles (IMN) could inhibit the undesired immune clearance and NK-activation during the blood circulation. Upon entering tumor tissue, overexpressed sialic acid on tumor cells competed for the phenylboronic acid (PBA) binding sites on IMN, triggering IgG exposure and stable adhesion to the cell surface, thereby conferring the in situ modification of the tumor cell surface with immune-activating signals. In 4T1 tumor-bearing mice, this nanosystem achieved a tumor growth inhibition rate of 56.8%, representing an 11.1-fold improvement over free IgG and a 1.3-fold enhancement relative to that of unmodified nBSA-PBA-IgG nanoparticles. A study by Wang et al. further confirmed the advantages of MPC for BBB crossing. They engineered an anti-PD-L1 nanodelivery system based on the MPC platform, integrating a pH-sensitive cleavable linker (MMfu) to enable a tumor microenvironment-responsive release. This design preserved MPC-mediated BBB transcytosis while achieving precise antibody release through pH-triggered MMfu cleavage in the acidic glioma microenvironment, thereby blocking the PD-L1/PD-1 immunosuppressive axis. In the brain metastatic lymphoma mouse model, the system enhanced intracerebral anti-PD-L1 concentrations 12.7-fold, promoted CD8⁺ T cell infiltration, and elicited an 83% tumor clearance ratesignificantly outperforming free antibodies (17%) and demonstrating synergistic crossing-drug release-immune activation. In a later study, Peng et al. subsequently exploited LAT1-mediated transport for antiglioblastoma therapy, developing a novel diblock zwitterionic polycaprolactone-poly­(4-(N,N-dimethylamino-N-acetyl sulfadiazine) benzoyl oligo (ethylene glycol) methacrylate) (denoted as PCL-PSDMA) copolymer that diverged from prior MPC-based platforms (Figure b). Self-assembled micelles of this copolymer achieved efficient BBB penetration via LAT1-mediated transcytosis. Given the pKa of sulfadiazine (6.5), PCL-PSDMA micelles underwent protonation and exhibited a positive surface charge in the slightly acidic tumor microenvironment (pH < 6.8), facilitating strong electrostatic attraction with negatively charged tumor cells for deep tumor penetration. This mechanism sequentially circumvented barriers imposed by systemic circulation, BBB, IFP, tumor cell membrane, and lysosomal degradation.

Current ZIP-based brain-targeted drug delivery systems predominantly exploit receptor-mediated transcytosis pathways (e.g., nAChR-targeted strategies) for CNS delivery. However, transcriptomic analyses of human and animal brain tissues have further revealed that receptor expression profiles at the BBB exhibit substantial heterogeneity across different diseases (e.g., glioma, neurodegenerative disorders, and brain metastases). − For instance, the expression level of transferrin receptor 1 (TfR1) is markedly elevated in the BBB and tumor cells compared to that in normal tissues, rendering it a crucial molecular target for tumor-targeted therapy and CNS drug delivery. Beyond TfR1, accumulating evidence indicates that glucagon-like peptide-1 receptor (GLP-1R) expression is markedly upregulated under aging and the associated neurodegenerative conditions. Remarkably, the administration of GLP-1R agonist was able to lead to functional recovery of the BBB in an aging mouse model of AD. On the other hand, the lactoferrin receptor (LfR) is highly expressed in brain endothelial cells, capillaries, and neurons associated with neurodegenerative disease and thus has been extensively explored as a vector for brain-targeted drug delivery via receptor-mediated transcytosis ^, , ^. Meanwhile, as mentioned above, nAChRs are widely distributed in brain tissues, with abundant expression particularly in brain capillary endothelial cells, and delivery strategies targeting nAChRs have demonstrated significant therapeutic enhancement effects in glioma and brain injury models. ,− Therefore, a strategy of paramount importance for precise and efficient CNS therapy is to tailor zwitterionic delivery systems to disease-specific pathophysiological characteristics (e.g., specifically overexpressed receptors or transporters on cerebrovascular endothelial or diseased cells) rather than depending on generic nAChR-mediated pathways.

2.3. Intravenous Zwitterionic Nanomedicines Target the Spleen

As the largest secondary lymphoid organ, the spleen is rich in antigen-presenting cells and lymphocytes and has emerged as a key target for vaccine development. However, due to their cholesterol-associated component properties, current lipid nanoparticles (LNPs) predominantly accumulate in the liver rather than the spleen following intravenous injection, which severely compromises the efficacy of spleen-targeted vaccines. , Separate data demonstrate that PEG-specific antibodies accelerate the accelerated blood clearance (ABC) of traditional LNPs (which contain PEGylated lipids), leading to reduced efficacy upon repeated administration. To enhance the spleen-targeting efficiency and serum stability of mRNA, Siegwart et al. reported a zwitterionic phospholipidation functionalization strategy capable of converting cationic polymers into zwitterionic phospholipidated polymers (ZPPs) (Figure a,b). Such a modification substantially augmented the serum stability and membrane fusion characteristics of ZPPs, facilitating targeted in vivo delivery of mRNA to both the spleen and lymph nodes. In recent work, Jiang et al. broke through the existing LNP paradigm by replacing cholesterol and PEGylated lipids with zwitterionic pyridine carboxybetaine (PyCB)-based ionizable lipids (denoted as ThrCo) to enhance the splenic tropism of LNPs and mitigate the ABC effect (Figure c–e). The enhanced hydrophilicity of the PyCB lipid improved LNP stability, redirecting a substantial portion of typically liver-accumulating LNPs to the spleen, which specifically enhanced the mRNA translation efficiency within this organ. Critically, the zwitterionic surface reduced non-specific protein adsorption in the bloodstream, thereby mitigating the accelerated blood clearance effect and improving vaccine bioavailability upon multiple injections. Their study revealed that compared to BNT162b2 LNPs from Pfizer-BioNTech, ThrCo LNPs exhibited a 4.5-fold increase in mRNA translation in the spleen. Compared with the previously reported anionic spleen-targeting 18:1 phosphatidic acid LNPs, ThrCo LNPs boosted mRNA translation in the spleen by more than 40-fold.

4.

(a) Phospholipidation strategy converting cationic polymers into zwitterionic mRNA carriers for targeted protein expression in spleen and lymph nodes. (b) Chemical structures of PAn-xPm polymers derived from different species of amines at physiological pH. Reproduced from ref . Copyright 2021, American Chemical Society. (c–f) Comparative organ distribution and translational activity of mRNA-LNPs: (c) BNT162b2, (d) anionic spleen-targeting 18PA, and (e) zwitterionic ThrCo formulations. Reproduced from ref . Copyright 2025, The American Association for the Advancement of Science.

Overall, zwitterion-based polymeric carriers have emerged as highly efficient tissue-targeted drug delivery platforms for intravenous administration. By virtue of their reversible membrane affinity, pH-triggered charge reversal, and exceptional protein-repellent properties, these nanocarriers effectively overcome multiple stringent biological barriers, substantially enhancing drug accumulation at target sites while minimizing systemic off-target toxicity.

3. Biological Barriers to Oral Administration

Oral administration is widely accepted by patients owing to its favorable safety profile, convenience, non-invasive nature, and high adherence. Oral drug delivery is consistent with the body’s physiological absorption mechanisms, thereby reducing systemic perturbations and adverse reactions. , Its noninvasive nature makes it preferable to the discomfort and inconvenience of injectable therapies. ,, However, owing to the presence of rigorous physiological barriers in the gastrointestinal (GI) tract, many oral drugs pose numerous challenges, including acid or enzymatic absorption, degradation and extreme pH-induced inactivation. Furthermore, the mucus layer and epithelial lining of the gastrointestinal tract constitute a formidable biomolecular barrier. The mucus traps large molecules to prevent penetration, while the epithelial tight junctions restrict paracellular transport, thereby limiting the systemic absorption of poorly permeable drugs. Finally, absorbed drugs undergo first-pass metabolism in the liver, which can significantly reduce their systemic bioavailability. Specifically, the barriers to oral absorption can be divided into biochemical barriers (lumen environment), mucosal barriers (the mucus covering the entire GI tract luminal wall), and cellular barriers (the tissue). ,,

To overcome these biological barriers mentioned above prior to reaching the target region, zwitterionic nanomaterials are promising oral delivery carriers, and given that the zwitterionic surface binds a dense hydration layer via Coulombic forces (e.g., ion–dipole interactions), immobilizing water molecules to form a biologically inert and stable solvation shell sulfobetaine traps 8× more water than ethylene oxide, which suppresses interactions with GI fluids, contents, and mucus. In addition, the close proximity of opposite charges on the surface results in negligible electrostatic interactions with ionic substructures in the GI tractsuch as bile salts, fatty acids, electrolytes, and mucin glycoproteinsthereby effectively avoiding nonspecific binding. , Hu et al. also investigated the transport efficiency of the poly­(lactic-co-glycolic acid) (PLGA)-based nanomedicine platform with various surface modifications [PEG, poly­(vinyl alcohol) (PVA) with different molecular weights and degrees of hydrolysis, Pluronic F127 (F127), and Polydopamine (PDA)] across the mucus and epithelial barriers. The size and zeta potential of the nanoparticles were characterized by dynamic light scattering (DLS). All nanoparticles exhibited uniform size distributions with hydrodynamic diameters primarily ranging from 200 to 300 nm. Although the particle sizes increased slightly upon modification with different polymers compared with unmodified PLGA nanoparticles, no significant differences in diameter were observed among the various modification systems. Furthermore, the results of zeta potential measurements indicated that compared with the unmodified PLGA nanoparticles (−13.0 ± 2.7 mV), the introduction of PVA, F127, or PDA coatings all caused a negative shift in zeta potential; in contrast, PEG modification significantly shifted the zeta potential toward the neutral value (−6.2 ± 1.7 mV). These divergent surface properties are anticipated to govern nanoparticle–mucus interactions, prompting subsequent investigations into mucus penetration, cellular uptake, and transepithelial transport across the various formulations. Consistent with these physicochemical characteristics, PLGA nanoparticles modified with zwitterionic PDA demonstrated superior mucus penetration and markedly enhanced cellular uptake relative to unmodified PLGA, PLGA-PVA, PLGA-PEG, and PLGA-F127 nanoparticles both in vitro and in vivo. Conversely, unmodified PLGA and PVA-coated PLGA nanoparticles exhibited strong mucoadhesive properties and mucus immobilization, which could be attributed to hydrogen bonding, hydrophobic interactions, and entanglement of PVA polymer chains with mucin fibers. Although the PLGA-PEG and PLGA-F127 nanoparticles displayed a relatively satisfactory mucus-penetrating capacity due to the neutral surface of PEG-PLGA and the hydrophilicity of F127, their neutral and negative surfaces also limited the amount of PLGA-PEG and PLGA-F127 nanoparticles taken up by the epithelial cells.

These studies demonstrated recent advances in oral zwitterionic nanomedicines for combating various diseases, elucidating the underlying mechanisms that enable efficient traversal of biological barriers (the mucus layer and intestinal epithelium). In vitro and in vivo investigations confirmed the therapeutic and diagnostic efficacy of these nanomedicines, which arose from their unique permeation mechanisms. These findings establish a solid foundation for the subsequent clinical translation.

3.1. Oral Zwitterionic Nanomedicines against Cancer

There is no denying that cancer has always been a difficult and global public health problem. , Currently, oral drug delivery systems for cancer therapy encompass a range of modalities, including chemotherapy, radiotherapy, immunotherapy, gene therapy, magnetothermal therapy, and microbial-based therapy. These approaches offer valuable references and possibilities for the development and clinical translation of oral nanomedicine. ,

For example, to achieve effective targeted drug delivery for colorectal cancer (CRC), Zhang et al. developed an oral CRISPR-Cas9 delivery system based on zwitterionic trimethylamine oxide (TMAO) and polysaccharide polymer-coated nanocomplexes that crossed the intestinal epithelial mucosal layer and disrupted the TRAP1 gene in CRC (Figure a). The directly linked positive and negative charges of the zwitterionic TMAO endow it with exceptional water-retaining and antiprotein-adsorption capacities, enabling it to potently suppress ice crystallization and to shield encapsulated proteins from urea-induced damage. After oral administration, the delivery system had the remarkable ability to accumulate in CRC tissues, due to its rapid penetration of the mucus layer and crossing of the epithelial cell barrier via transcytosis mediated by the TMAO transporter OCTN2 (Figure b,c). As a result, the oral CRISPR-Cas9 delivery system increased the sensitivity to ICB therapy and ultimately demonstrated remarkable therapeutic efficacy against CRC. Alternate studies also reported that a water-soluble zwitterion OPDEA was essentially charge-neutral at physiological pH and non-interactive with proteins, yet it engaged in low-affinity binding to plasma-membrane lipids that triggered rapid adsorption-mediated endocytosis and transcytosis in both endothelial and tumor cells. After oral administration, the block copolymer OPDEA-poly­(ε-caprolactone) (OPDEA-PCL) polymeric micelles persisted for prolonged periods in the gastrointestinal tract, traversed the intestinal mucus layer, adhered to enterocytes, and were translocated across the epithelium via a non-lysosomal, transcytosis-mediated transepithelial transport into blood circulation for tumor accumulation (Figure d). This sequential process enabled efficient delivery of paclitaxel to tumor tissue, conferring an antitumor efficacy that surpassed that of intravenously administered PEGylated analogues. In the Sprague–Dawley (SD) rat model, the bioavailability of orally loaded PTX-loaded OPDEA micelles was 28.73%, which was 4.6-fold that of PEG micelles and 11.8-fold that of free PTX (Figure e,f).

5.

(a) Schematic illustration of the zwitterionic TMAO-modified oral CRISPR-Cas9 delivery system HA-TMAO-modified PBAE-based DNA vector (HTPBD). (b) The flow cytometry plots and confocal laser scanning microscope images of Caco-2 cells after incubation with different PBD formulations (scale bar, 20 μm). (c) Representative flow cytometry plots of NIH-3T3 cells incubated with different PBD formulations. Reproduced from ref . Copyright 2025 Springer Nature. (d) Schematic illustration of OPDEA-PCL chemical structure and its micelles. (e) The confocal laser scanning microscope images of the jejunum cross-section (scale bar, 200 μm). (f) The summary of averaged PTX concentration in plasma and the corresponding pharmacokinetic parameters (n = 3); SD rats. Reproduced from ref . Copyright 2022 John Wiley and Sons.

3.2. Oral Zwitterionic Nanomedicines against Diabetes

Diabetes mellitus (DM), a chronic metabolic disorder of global prevalence, remains best managed with insulin-based therapy, which is still the most effective treatment available. In contrast to conventional treatment with periodic insulin injections, oral administration of protein drugs presents a promising therapeutic alternative for diabetic patients.

To concurrently overcome the mucus and epithelial barriers of the gastrointestinal tract, recent studies have predominantly focused on zwitterionic micelles as a platform to enhance the oral bioavailability of encapsulated insulin. In earlier times, Cao et al. reported a zwitterionic micelle DSPE-PCB by conjugating poly-carboxy betaine (PCB) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) lipid, enabling insulin penetration through the mucus and efficient transporter-mediated epithelial absorption and bypassing tight junctions (Figure a). Unlike conventional surfactants, this work first revealed that these zwitterionic micelles exhibited an ultra-low critical micelle concentration (CMC <10^–6 mM), precluding their dissociation at tight-junction proteins and on cell membranes. In the diabetic rat model, the bioavailability of insulin loaded on DSPE-PCB micelles achieved 42.6%, which was higher than that of PEG micelles of 8.56% (Figure b,c). To increase the transcytosis and absorption of zwitterionic modifications, Qian et al. engineered zwitterionic nanoparticles modified with ursodeoxycholic acid (UDCA) for insulin delivery that exploited the apically expressed zwitterion carboxy betaine (CB) receptors (proton-assisted amino acid transporter) and UDCA receptors (apical sodium-dependent bile acid transporter) on enterocytes, enabling efficient receptor-mediated transcytosis across the intestinal epithelium (Figure d). The nanoparticles also exhibited robust hepatic tropism and glucose responsiveness, enabling efficient prandial glycemic control and enhancing intrahepatic glucose utilization. Moreover, they also used a similar method to co-delivery insulin and berberine. In vivo, the coadministration of CB and UDCA enabled sustained intestinal release and prolonged circulation of insulin and berberine, synergistically maintaining glycemic control for approximately 10 h. However, for treating DM, it is crucial to ensure sustained insulin release for prolonged periods to prevent fluctuations in blood glucose (BG) levels. For this purpose, Gu et al. synthesized an amphiphilic di-block copolymer PPF, comprising a hydrophilic zwitterionic polycarboxybetaine (PCB) segment and hydrophobic 4-carboxy-3-fluorophenylboronic acid-modified poly­(2-aminoethyl methacrylate) (FPBA-modified PEA). Micelles self-assembled from poly­(propylene fumarate) (PPF) and the insulin–Zn²⁺ hexamer exhibited a worm-like morphology, small hydrodynamic diameter, and a zwitterionic surface that collectively enhanced intestinal absorption, affording an oral bioavailability of 18.9% (Figure e). After absorption, the formulation further established a glucose-responsive hepatic insulin depot. Post-prandial hypoglycemia triggered boronate ester formation between glucose and the FPBA pendants, weakening insulin–polymer affinity and accelerating insulin release. In both streptozotocin-induced type 1 diabetic and non-obese diabetic (NOD) mouse models, the micelles effectively maintained plasma glucose within the normoglycemic range. The glucose-responsive intelligent oral insulin formulation developed in this study significantly enhances the convenience of insulin therapy. A single oral dose ensures 24 h basal BG stability and effective management of postprandial glucose fluctuations. This approach effectively mitigates the key limitations of conventional subcutaneous insulin injections, such as low bioavailability, poor patient compliance, and a high risk of hypoglycemia. In a similar fashion, Li et al. synthesized poly­[2-(methacryloyloxy)­ethyl choline phosphate] (PMCP)-based glucose-responsive polyzwitterionic nanoparticles (B-CP/INS NPs) for oral delivery of insulin, which could overcome the mucus barrier and cross the epithelial cell layer, owing to the targeting and specific CP-PC interaction between polyzwitterionic PMCP and the epithelial cell membrane.

6.

(a) Schematic representation of DSPE-PCB micelles for oral delivery of insulin. (b,c) Pharmacological performance and bioavailability of DSPE-PCB/insulin capsule, Polysorbate 80/insulin capsule, and native insulin in diabetic rats after oral gavage (n = 6 biologically independent animals, means connected). Reproduced from ref . Copyright 2020 John Wiley and Sons. (d) Components and fabrication of UC-CMs@ins. Reproduced from ref . Copyright 2024 John Wiley and Sons. (e) Schematic illustration of glucose-responsive worm-like micelles for oral insulin delivery in type 1 diabetes. Reproduced from ref . Copyright 2024 Springer Nature.

In type 2 DM, exendin-4 achieves glycemic efficacy comparable to insulin; moreover, its glucose-lowering action is glucose-dependent, resulting in a lower hypoglycemia risk. , To surmount the intrinsic physiological barriers confronting the oral delivery of exendin-4. In their study, Chen et al. surface functionalized metal-organic framework (MOF) nanoparticles with a zwitterionic hydrogel layer, with the goal of transferring the drug exendin-4 into the plasma. They tested the hypoglycemic effect of the drug through oral administration in a diabetes rat model and showed that plasma exendin-4 remained elevated over 8 h, evoking a marked increase in endogenous insulin secretion and a significant hypoglycemic effect, with a relative pharmacological availability of 17.26%, attributed to enhanced mucus penetration and cellular internalization of the zwitterionic hydrogel shell. Compared to other methods, Liu et al. developed an in situ polymerization strategy for oral feeding, in which a ZIP network was grown directly on the protein (bovine serum albumin, insulin, and antibodies) surface by one-pot mixing of the protein with anionic, cationic, and zwitterionic monomers, followed by rapid initiation, affording a markedly simplified preparation and purification workflow compared with conventional grafting approaches.

3.3. Oral Zwitterionic Nanomedicines against Colitis

Inflammatory bowel disease (IBD) is a complex, heterogeneous, immune-mediated inflammatory condition with a multifactorial aetiopathogenesis, involving imbalanced interactions between disrupted intestinal barriers, gut microbiota dysbiosis, and uncontrolled mucosal inflammation. − In the current century, IBD has evolved into a global health concern. Although oral nanomedicine has been gradually leveraged in the treatment of IBD, the targeted gut delivery of overcoming the GI barriers remains a significant challenge. It has been demonstrated that the coexistence of oppositely charged moieties on zwitterionic surfaces can induce a robust hydration layer, conferring resistance to gastric acid degradation and reducing nonspecific intestinal adsorption. ,,

To overcome the poor mucosal retention of conventional zwitterions, poly­(choline phosphate) and poly­(tertiary amine oxide) (PTAO)bearing inverted dipole vectorswere established as reported by Shen et al. These polymers reversibly coordinated with cell membrane phosphatidylcholine, under went efficient uptake by enterocytes and macrophages in ulcerative colitis, and subsequently delivered superoxide dismutase (SOD) and catalase (CAT) to mitochondria for synergistic ROS elimination (Figure a–c). In addition to oral protein therapeutics, probiotic formulations with demonstrated efficacy against inflammation, obesity, neoplasia, and autoimmune disorders represent promising candidates for IBD intervention. Building on these findings, Hu et al. demonstrated that tertiary amine N-oxide zwitterionic derivatives were efficiently internalized by probiotic bacteria and exploited this property to engineer Escherichia coli Nissle 1917 (EcN) loaded with a CO/H₂S-releasing copolymer for targeted intestinal gasotransmitter delivery, and hydrophilic segments of the copolymer comprised zwitterionic triethylamine N-oxide residues ODEA (Figure d). The engineered probiotics enhanced intestinal colonization and on-demand CO/H₂S liberation within inflamed mucosa to downregulate inflammation, restored intestinal barrier integrity, and reshaped gut microbiota. Critically, this strategy could reduce neuroinflammation via the gut–brain axis and mitigate anxiety- and depression-like behaviors in IBD mice.

7.

(a) Schematic of ROS-degradable PTAO-coated nanocage synthesis. (b) Flow cytometry analysis of ROS levels in untreated or H₂O₂-treated Caco-2 cells under different treatment conditions. (c) Colocalization of poCAT-FITC (green) and poSOD-Cy5 (red) in mitochondria (cyan) of live Caco-2 cells, imaged by confocal microscopy. Reproduced from ref . Copyright 2025 American Chemical Society. (d) Scheme illustrating the preparation of POSR@EcN via feeding EcN with POSR copolymers. Reproduced from ref . Copyright 2025 John Wiley and Sons.

4. Biological Barriers to Pulmonary Inhalation Administration

Inhaled drug delivery enables targeted treatment of primary respiratory disorders and systemic diseases with pulmonary involvement, for instance, asthma, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), bronchopulmonary dysplasia, and lung cancer, which is among the most straightforward methods for localized lung delivery. ,,− Its non-invasive nature has made it a popular choice, offering advantages such as avoidance of hepatic first-pass metabolism, low enzymatic metabolism, and a large absorption surface. By allowing drugs to directly enter systemic circulation via the alveolar region of the lungs, pulmonary drug delivery can result in a significantly more rapid therapeutic onset compared to other administration methods. , Additionally, the COVID-19 pandemic further propelled the demand for inhalable therapies. The in vivo delivery efficiency of inhaled pulmonary drug delivery systems is constrained by multiple physiological barriers: (i) The complex biochemical microenvironment formed by airway mucus and pulmonary surfactantscharacterized by obstruction from the mucin network, electrostatic interactions between mucin components and drugs, and dynamic pH fluctuationsimpairs the diffusivity and stability of the delivery system. (ii) Pulmonary clearance machineries, including mucociliary clearance and the recognition and phagocytosis of foreign particulates by alveolar macrophages, significantly impede the effective absorption and local accumulation of therapeutics. , Zwitterionic nanomaterials confer distinct advantages in circumventing the aforementioned physiological barriers. This section examines the mechanistic underpinnings by which these systems penetrate pulmonary defense mechanisms and strategies to enhance the accumulation of therapeutics at the target pulmonary lesions.

4.1. Zwitterionic Polymers for Lung Mucus Penetration

Recent studies have highlighted the exceptional role of ZIPs as advanced platforms for overcoming the physiological mucosal barriers encountered during pulmonary drug delivery. Among these materials, PDA, a biomimetic polymer derived from marine mussel proteins, has garnered significant attention for its exceptional biocompatibility and biodegradability. , PDA can form a zwitterionic surface coating on particles, which mitigates interactions with negatively charged mucins and thereby enhances mucus penetration. Furthermore, PDA possesses abundant phenolic hydroxyl groups that endow it with potent reactive oxygen species (ROS)-scavenging capabilities, rendering it highly suitable for tackling both physical and biochemical hurdles associated with pulmonary inflammation. Inspired by this, Yang et al. designed an inhalable nanocapsule system based on transformable PDA nanocapsules that provides efficient penetration of the airway mucus barrier and scavenges ROS, effectively mitigating lung inflammation. Among these, the smallest nanocapsule demonstrated superior mucus penetration, likely due to its deformability and hollow structure.

Acute respiratory distress syndrome (ARDS) is a severe respiratory infectious disease. In addition to the aforementioned mucus barrier, the accumulation of bronchoalveolar lavage fluid (BALF) in the alveolar area further reduces the efficiency of drug delivery to the lungs. Passive approaches of modifying the surface characteristics with polyethylene glycol functionalization or a zwitterionic surface have limitations in overcoming the self-defensive respiratory barriers. Hong et al. presented a novel active approach for drug delivery to the lung alveoli that overcomes these limitations. They developed nanocomplexes coated with ZIPs and nitric oxide (NO) donor, which not only avoided being trapped in the mucus layer of the respiratory tract under the hydration layer of zwitterionic moieties, enabling them to reach the alveoli, but also released NO gas to provide a power source that gave additional mobility to nanocomplexes and maximized the efficiency of delivery to the alveoli epithelium without being trapped in BALF (Figure a). In vivo, the nanocomplex-treated group achieved a marked reduction in pulmonary inflammation score, proven by a more than threefold decrease compared to the LPS-treated group, indicating its ability to repair pneumonic damage and restore the structure of alveolar branches (Figure b). This design strategy exhibits enhanced pulmonary delivery efficiency and an anti-inflammatory effect, alleviating symptoms in the ARDS disease model.

8.

(a) Schematic illustration of in situ NO release analysis in a mucus environment. (b) Quantitative analysis of murine pulmonary inflammation. Data are mean ± SEM calculated for each group. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (one-way ANOVA with Turkey’s correction, all experiments were conducted independently). Reproduced from ref . Copyright 2024 Elsevier. (c) Schematic of DLPE-Poly­(CMBA) ZIP-lipid formulation with lipid-anchored ZIP for enhanced nebulizer stability and inhaled mRNA delivery to healthy and muco-obstructed mouse lungs. (d) In vitro transfection efficiency and encapsulation efficiency of ZIP-LNPs before and after nebulization evaluated in the DOE study (n = 3 repeat measurements). Reproduced from ref . Copyright 2024 American Chemical Society.

Beyond sulfobetaine zwitterion-based systems, LNPs formed from ZIP containing carboxybetaine methacrylate have shown considerable promise for mucopenetrant drug delivery. Danial G. Anderson et al. first reported the use of these polymers to stabilize LNPs for inhaled mRNA delivery. Through formulation optimization utilizing design-of-experiment methodologies, they identified that the optimized ZIP-lipid-modified lipids (ZIP-LNP/9.2) formulation demonstrated improved inhaled mRNA delivery in both healthy and muco-obstructed mouse lungs (Figure c,d). After nebulization, ZIP-LNP/9.2 maintained its structural integrity, with a stable hydrodynamic diameter of ∼200 nm. This dimensional characteristic enabled it to effectively evade the nonspecific clearance by alveolar macrophages (a size around 1 μm is best for macrophage phagocytosis). Moreover, the rapid mucus penetration of ZIP-LNP/9.2 effectively minimized their phagocytosis by alveolar macrophages, thereby reducing their clearance rate in lung tissue, potentially, which facilitated deeper penetration and prolonged retention of the nanoparticles in the lungs, thereby significantly enhancing the efficiency of mRNA pulmonary delivery. Of note, ZIP-modified liposomes encapsulating small molecules demonstrated excellent stability when compared to PEG-modified liposomes, which required substantial amounts of cholesterol to stabilize the liposome and prevent drug leakage. This is attributed to a strong surface hydration (superhydrophilicity) of ZIPs. In a similar fashion, 2-methacryloyloxyethyl phosphorylcholine polymer brushes efficiently prevent mucin adsorption at various pH levels. Surface chemical modification can tune these interactions; for example, installing phenylboronic-acid groups on the surface strengthens binding to mucin sialic acid at low-pH conditions.

Noticeably, although the modification of ZIPs could reduce mucin adsorption by suppressing mucin-nanocarrier interaction, the transport of nanocarrier remains highly restricted in pulmonary diseases with significantly elevated mucus viscosity, such as CF and COPD. A combination strategy, as reported by Pan et al., has been shown to improve mucus penetration and therapy effectiveness by reducing mucus viscosity and mucin retardant. These formulations consisted of N-acetylcysteine (a mucolytic agent), which was embedded in the zwitterion nanoparticles. Once the nanoparticles reached the mucus, the embedded N-acetylcysteine was released and could break the disulfide bonds and decreased the mucus viscosity, significantly promoting the mucus penetration performance and enhancing epithelial cell uptake.

Zwitterionic drug delivery systems for pulmonary administration continue to face significant challenges in simultaneously achieving optimal mucosal penetration and cellular internalization. The fundamental difficulty lies in establishing an effective equilibrium between these two critical parameters. Future research should focus on active targeting strategies, leveraging molecular recognition mechanisms to enhance cellular uptake. Additionally, the implementation of artificial-intelligence-driven platforms to optimize formulation parameters represents a promising approach to minimize off-target distribution while maximizing therapeutic efficacy.

5. Zwitterionic Polymers for Other Physical Biological Barriers

Alternative localized modalitiese.g., transdermal, intraperitoneal, intratumoral, or depot implantationcircumvent vascular transit, permitting direct nanoparticle–tissue engagement while curtailing systemic exposure and clearance. , Such localized delivery routes allow nanoparticles to be designed for direct tissue engagement, yet each route imposes route-specific extracellular and cellular hurdles that must be surmounted for efficient penetration and trafficking. , This section aims to examine the key biological barriers faced by drugs delivered via the aforementioned injection routes, with a focus on the application and unique advantages of zwitterionic nanomaterials in overcoming these barriers.

5.1. Zwitterionic Polymers for Transdermal Drug Delivery

As the third major drug delivery route following oral and parenteral administration, transdermal drug delivery systems confer advantages including bypassing hepatic first-pass metabolism, high absorption efficiency, stable plasma drug concentrations, and targeted delivery. , However, the skin, serving as a natural protective barrier that isolates the body from external substances, contains keratins and tightly packed hydrophobic layers of lipids, which significantly restrict the permeation of hydrophilic drugs and macromolecules. In a transdermal drug delivery system, microneedle technology has received considerable attention research owing to its minimally invasive and convenient self-administration with enhanced transdermal transport. , Zwitterionic polysulfobetaine-doped microneedles effectively penetrate porcine skin while preventing denaturation and aggregation of loaded proteins. Besides microneedles, iontophoresis can also increase skin permeability; combining it with chemical penetration enhancers has been a central theme in transdermal delivery. Kirjavainen et al. observed that pretreatment of the skin with zwitterionic egg lecithin increased the iontophoretic transdermal mannitol flux about three-fold compared to iontophoretic control without pretreatment. They attributed this phenomenon to the fluidization of stratum corneum lipid bilayers by EPC’s unsaturated fatty acids, which reduced the skin’s overall permeability barrier.

Shen et al. developed a highly skin-permeable polyzwitterionic polymer, poly­[2-(N-oxide-N,N-dimethylamino)­ethyl methacrylate] (OP), for non-invasive transdermal delivery of macromolecular therapeutics (insulin). In the acidic skin surface microenvironment, OP underwent protonation to acquire cationic character, thereby promoting enrichment within the stratum corneum lipid matrix (Figure a,b). Upon reaching deeper epidermal layers with a normal physiological pH, the polymer transitioned to a neutral polyzwitterion state that facilitates “hopping” along cell membranes, thereby circumventing intracellular enzymatic degradation (Figure c,d). This mechanism of pH-dependent charge conversion in the ZIP OP precisely harnessed the skin’s physiological pH gradient to enable rapid transdermal penetration and subsequent access to the lymphatic and circulatory systems. In streptozotocin (STZ)-induced type 1 diabetic mice, the insulin conjugate (OP-I) exhibited a hypoglycemic effect comparable to that of subcutaneous insulin injection. Intraperitoneal glucose tolerance tests confirmed that topical OP-I pretreatment enabled diabetic mice to achieve peak BGLs of 330 mg dl^–1 at 30 min and gradually declined to ∼100 mg dl^–1 within 1 h, remaining normoglycaemic thereafter. Healthy control mice showed comparable peak BGLs but failed to normalize (>200 mg dl^–1 at 2 h). In contrast, diabetic mice receiving topical insulin or PEG-I developed sustained hyperglycemia (∼600 mg dl^–1). Furthermore, topical OP-I demonstrated excellent biocompatibility, causing no skin irritation, morphological changes, inflammatory response, or systemic toxicity in both mouse and porcine models, with no adverse effects on hematological or biochemical parameters. These results demonstrated that transdermal OP-I exhibited superior glycemic control efficacy and biosafety compared with other therapeutic approaches.

9.

(a) Molecular dynamics simulations of OP-I with SC lipid interactions under different pH conditions. (b) The diffusivities of OP-I on SC lipids under pH 5.5 and pH 7.0 conditions. (c) Time-dependent redistribution of OP-ICy5 on HaCat cell membranes. (d) Representative CLSM images of OP-ICy5 transfer from OP-ICy5-pretreated HaCat cells to acceptor HaCaT-GFP cells. Reproduced from ref . The images are representative of n = 3 independent experiments. Scale bars, 50 μm (c (left), d (left)), and 20 μm (c (right) and d (right)). Copyright 2025 Springer Nature.

5.2. Zwitterionic Polymers for Intraperitoneal Drug Delivery

The peritoneal cavity offers an effective route for systemic drug delivery due to its large surface area, abundant vascularization, rapid absorption, and lymphatic-assisted transport. , However, drugs encounter multiple barriers prior to vascular access. Generally, small-molecule drugs permeate the visceral peritoneum and are absorbed via the mesentery and omentums into the portal venous circulation. In contrast, macromolecules primarily cross the parietal peritoneum to be absorbed through the lymphatic vessels, thereby bypassing hepatic first-pass metabolism. , Each of these steps significantly influences the ultimate absorption and delivery efficiency of drugs to their target tissues. Therefore, intraperitoneally injected nanoparticles should be engineered to promote high tissue affinity and penetration. Panthan et al. utilized the enhanced cellular uptake and opsonization-resistant properties of zwitterions to develop a novel zwitterionic triblock copolymer strategy to deliver anticancer drug doxorubicin and a deep-tissue-penetrable near-infrared IR-780 biomarker by intraperitoneal administration. These zwitterions exhibited enzymatic biodegradability and biocompatibility. Live-cell lysotracker-mediated imaging confirmed controlled release of DOX-loaded ZIPs and 3-fold to 4-fold higher cellular uptake than free DOX in breast cancer and ovarian cancer cell lines. In vivo biodistribution revealed prolonged blood circulation and enhanced organ retention over 72 h compared with free IR780.

5.3. Zwitterionic Polymers for Intratumoral Drug Delivery

For cancer therapy, intratumoral delivery represents the most direct approach in which nanoparticles are injected directly into the tumor. Intratumoral delivery can address cancers with physically accessible lesions, such as melanoma, liver cancer, and pancreatic cancer. − However, intratumoral injection is not feasible for deep-seated tumors or multiple metastases. Notably, even with direct intratumoral administration, nanoparticle drug delivery systems must prioritize efficient intratumoral transport to ensure the coverage of all cancer cells. Deep tumor penetration is primarily constrained by three physiological barriers: dense extracellular matrix restricting diffusion, elevated interstitial fluid pressure promoting rapid clearance, and preferential uptake/sequestration by tumor-associated macrophages. ,,

In order to boost the antitumor efficacy of PTT by promoting cellular uptake and tumor retention of PTT-carrying nanoparticles, Chiu et al. formulated IR780-loaded PLGA nanoparticles covered with the zwitterionic di-block copolymer. With solution pH being reduced from pH 7.4 to 6.0, the zeta potential of IR780-carrying PMHPNs from −18.9 to +2.4 mV (nearly neutral) was due to the acid-triggered protonation of the imidazole group to facilitate colloidal aggregation. The cargo-loaded PMHPNs capable of undergoing acidity-activated surface charge transition as well as colloidal aggregation could effectively promote their cellular uptake within TRAMP-C1 cells ex vivo.

5.4. Zwitterionic Polymers for Depot Implantation

Osteoarthritis (OA) is a chronic joint disease that causes the gradual deterioration of articular cartilage. Intra-articular injections are a first-line conservative option for patients with an ineffective or poor tolerance to oral pharmacotherapy. Although direct intra-articular injection can increase local drug bioavailability and reduce adverse systemic side effects, drugs administered in this manner are facing a major challenge in OA treatment, which is the limited penetration and delivery efficiency of drugs to cartilage and chondrocytes due to the rapid clearance of drugs through synovial fluid in joints and the osmotic barrier of the cartilage extracellular matrix (ECM). A growing body of literature presents compelling evidence for the notable effectiveness of zwitterionic surfaces in resisting permeating synovial fluid in osteoarthritis therapy. Zwitterionic entities display an extraordinary affinity for water molecules, allowing the formation of a resilient hydration layer that resists dehydration and sustains elevated pressures. More importantly, OA causes irreversible damage to cartilage due to increased mechanical friction in the joints; therefore, restoration of joint lubrication is essential for treatment. Based on this, Cui et al. fabricated highly lubricated and anti-senescence drug Met-loaded hydrogel microspheres through the radical polymerization of zwitterion sulfobetaine (SB)-modified hyaluronic acid methacrylate. The copolymer contained a large number of SB and carboxyl groups that could provide a high degree of lubrication through hydration and encapsulated Met by electrostatic loading interactions. The tribological tests confirmed that the application of SB-modified microspheres effectively enhanced lubrication, even during the gradual biodegradation of the hydrogel microspheres. This result can be attributed to the inherent dipole moment between quaternary ammonium cations and sulfonate anions, which facilitates the formation of a dense hydration layer on the microsphere surface, leading to a significant reduction in the shear stress between relatively moving surfaces. The use of the SB group for enhancing hydration lubrication was also reported by Li et al., who developed a dual-bionic photothermal nanozyme by modifying molybdenum disulfide (MoS₂) with Mg²⁺-doped polydopamine and coating with polysulfobetaines to mimic antioxidases/hyaluronan synthase for OA therapy. Zheng et al., on the other hand, developed hyaluronic acid (HA)-based amphiphilic nanospheres (HA-MPC) surface-functionalized with choline phosphate groups to enhance joint lubrication. These nanospheres were synthesized via the thiol-functionalization of HA with hexadecylamine, followed by MPC conjugation using thiol–ene click chemistry. The resulting amphiphilic derivatives self-assembled into nanospheres through hydrophobic interactions. The HA-MPC formulation reduced the coefficient of friction by 40% compared to pure HA via a hydrated lubrication mechanism and demonstrated remarkable efficacy in improving biocompatibility, upregulating anabolic genes, and downregulating catabolic and pain-related mediators.

6. Conclusions and Final Remarks

This perspective systematically examines the mechanisms and prospects of ZIP-based drug delivery systems in overcoming diverse biological barriers, providing a critical reference for targeted delivery design. However, the lack of standardized methods for assessing zwitterionic material penetration impedes homogeneous cross-system comparisons, hindering mechanistic elucidation and performance optimization. Although foundational studies of zwitterionic materials have achieved remarkable advances, their translational progress into clinical applications lags considerably behind that of lipid nanoparticles (LNPs). As documented in ClinicalTrials.gov, fewer than five clinical investigations involving zwitterionic materials have been registered to date, substantially fewer than the approximately 20 trials for LNPs, among which are the BNT162b2 and mRNA-1273 vaccines authorized for emergency use in late 2020. This gap highlights the formidable obstacles confronting the transition of zwitterionic materials from the laboratory bench to clinical implementation. Specifically, pH-sensitive zwitterions may compromise their anti-fouling properties under specific pH conditions, limiting utility across diverse mucosal milieus. Achieving homogeneous surface density across zwitterion-coated carriers presents a significant manufacturing challenge, which can impede production reproducibility at scale. Most critically, the design of nanocarriers for drug delivery is constrained by a central paradox: surfaces optimized for mucus penetration (electroneutral and hydrophilic) are conversely suboptimal for epithelial cell uptakea limitation that can only be mitigated by incorporating cationic motifs or targeting ligands, a capability lacking in conventional zwitterionic platforms. Future research should integrate data science with clinical translation imperatives to advance next-generation drug delivery systems with efficient physiological barrier penetration.

• (1)Leveraging large libraries and machine learning

Future nanomedicine advances will benefit from integrating high-throughput screening with machine learning, substantially enhancing nanoparticle design efficiency and clinical translation potential. However, the expansive design space of zwitterionic delivery systemsencompassing composition, surface chemistry, particle size, and other parameterscoupled with costly, low-throughput in vivo screeningseverely constrains their development. Therefore, systematically elucidating correlations between zwitterionic properties and tissue barrier heterogeneity biomarkers while accelerating the screening of efficient candidates represents a key challenge.

Artificial intelligence (AI)-based predictive modeling optimizes the design of tissue-penetrating drug delivery systems through the integration of carrier formulation parameters, drug carrier behaviors, and biological factors, thereby enabling the faster and cheaper development of therapies that cross physiological barriers and target specific tissues. In parallel with AI-assisted design, silico optimization platforms offer a powerful and systematic approach to rapidly testing and refining inhalable LNP formulations. For example, a systematic evaluation process for pulmonary nebulized formulations could leverage the design of experiments (DOE) method to screen the molar ratios of zwitterionic polymers (ZIPs), phospholipids, and cholesterol, as well as optimize the ZIP length and phospholipid identity, thereby obtaining an optimal formulation with high mRNA encapsulation and transfection efficiency post-nebulization, along with minimized LNP size. Additionally, by leveraging high-throughput platforms, AI dramatically expedites the analytical and predictive workflows for large-scale polymer repertoires. Complementarily, sophisticated barcoding strategies provide a robust avenue for more efficient and economical in vivo high-throughput screening, enabling streamlined large-scale biological testing.

• (2)Leveraging evolving clinical datasets

Designing clinically translatable drug delivery systems necessitates patient-specific tissue-targeting strategies that elucidate lesion microenvironment biology to guide efficient nano-therapy development. Modern omics technologies, including single-cell sequencing, spatial omics, and high-resolution imaging, precisely dissect lesion heterogeneity, surface receptor expression profiles, and nanoparticle uptake-associated genetic signatures, thereby elucidating interpatient pathophysiological impacts on nanomedicine delivery and informing optimization of tissue targeting, cell-binding efficiency, and internalization capacity. Moreover, large-scale clinical trial data from nanomedicine, coupled with artificial intelligence and machine learning, can refine nanomaterial physicochemical design to enhance barrier penetration, target cell recognition, and endocytic efficiency.

In conclusion, this account summarizes the significant efforts invested in advancing the transport of ZIP-based systems across biological barriers. While the overall delivery efficiency achieved to date is often suboptimal, future breakthroughs in clinical translation are anticipated through the development of artificial-intelligence-guided design and synthesis of ZIPs.

The authors declare no competing financial interest.