Subcellular organelle-targeted strategies hold great promise in cancer therapy. Peptide nanofibers can induce lysosomal membrane permeabilization (LMP) and microtubule disruption, yet their in vivo delivery remains challenging. Here, we report a matrix metalloproteinase-2 (MMP-2)-responsive shape transformable nanosystem (CpA) that self-assembles from the amphiphilic conjugate Ce6-pep-iABS, comprising the photosensitizer chlorin e6 (Ce6) and the carbonic anhydrase IX (CA IX) inhibitor 4-(2-aminoethyl) benzenesulfonamide (ABS) linked via an MMP-2-cleavable peptide. Upon reaching tumors, CpA transforms from spherical nanoparticles into nanofibers, enabling deep penetration and long-term retention in tumor. The released ABS segments continuously inhibit CA IX to reverse extracellular acidosis and alleviate immunosuppression. Crucially, the transformed nanofibers exhibit enhanced cellular uptake and induce sequential LMP and microtubule disruption, which synergizes with photodynamic therapy (PDT) to amplify immunogenic cell death (ICD), activate robust antitumor immunity, and establish long-lasting immunological memory. This synergistic effect significantly inhibits tumor growth and prevents tumor recurrence and metastasis, presenting an innovative paradigm for multimodal cancer therapy by integrating sequential organelle targeting, tumor microenvironment modulation, and intensified PDT.
BACKGROUND:Localized biofilm-associated infections such as chronic wounds, osteomyelitis, and implant infections remain difficult to treat with systemic antibiotics amid rising resistance. Hydrogel delivery may enhance bacteriophage (phage) therapy by protecting phages, prolonging residence, and enabling controlled release. This systematic review summarizes in vivo evidence for hydrogel-mediated phage delivery and its translational relevance. METHODS:Following PRISMA 2020, PubMed, Web of Science were searched to 14 January 2026 using MeSH terms for bacteriophages, hydrogels/local delivery, and in vivo or clinical applications. Eligible studies reported original in vivo animal or human data; in vitro-only work was excluded. RESULTS:Nineteen studies met criteria: three clinical and sixteen preclinical. Clinical use included fracture-related, burn wound, and prosthetic joint infections treated with commercially available phage preparations in hydrogels. In a single compassionate-use fracture-related infection case managed with concurrent surgical debridement and systemic antibiotics, infection control without recurrence and good bone healing were observed at one year; locally applied phages remained detectable for approximately 72 h, indicating in vivo release and surgical compatibility, although the independent contribution of the hydrogel-phage component could not be isolated. Preclinical studies tested 28 phages against six bacterial species via topical, injected, intraoperative, oral, or irrigation delivery. Consistent benefits occurred in burn (n = 6) and wound/soft-tissue models (n = 5) with lower bacterial load, improved healing, and increased survival in two burn studies. Bone/joint models (n = 4) showed partial reduction but inconsistent eradication. Other studies demonstrated ~2000-fold pathogen reduction in colitis and decreased bacterial and inflammatory markers in endodontic infection. CONCLUSIONS:Hydrogel-based local phage therapy is a feasible strategy for infection control No major adverse effects were reported in the included studies, although safety reporting was limited. Standardized in vivo comparisons and clinical trials are needed to optimize delivery and dosing.
Effective pulmonary drug delivery faces formidable physiological barriers，particularly mucociliary clearance, phagocytosis by alveolar macrophages, and the complex pathological microenvironment. To address these challenges, inhaled biomimetic carriers have emerged as a highly advantageous platform for drug delivery. By leveraging characteristics derived from their biological origins, these carriers inherently possess the capacity to bypass specific pulmonary defense mechanisms, thereby significantly enhancing the efficiency of drug delivery in the treatment of respiratory diseases. This review outlines the physiological barriers in the lungs to highlight the necessity of overcoming them. The following sections focus on the latest research and clinical progress of various inhaled biomimetic delivery vehicles, which will contribute to the strategic development of inhaled drug delivery system platforms and provide insights for achieving precise and effective treatment of respiratory diseases.
Growth factors (GFs) are signaling molecules that play pivotal roles in tissue engineering by regulating essential biological processes such as cell proliferation, differentiation, migration, and survival. Despite their remarkable therapeutic potential, the clinical translation of natural GFs remains hindered by several intrinsic limitations, such as high production costs, poor stability and short half-life in vivo, insufficient targeted delivery and controlled release capabilities. To address these challenges, increasing attention has been directed toward growth factor-mimetic peptides derived from the bioactive domains of natural GFs. In particular, self-assembling GF-mimetic peptides can spontaneously organize into ordered nanostructures under physiological conditions, enabling enhanced stability, multivalent bioactivity, and localized presentation of signaling motifs while partially recapitulating the functions of native GFs. In this review, we systematically summarize the classification, structural characteristics, and biological functions of self-assembling GF-mimetic peptides and discuss recent advances in incorporating single or multiple GF-derived active epitopes into various biomaterial platforms. We further highlight how the synergistic or additive effects of these multifunctional systems contribute to enhanced tissue repair and regeneration. In addition, this review emphasizes current design strategies for constructing GF-mimetic peptides, focusing on the relationship between molecular design, self-assembly behavior, and bioactivity. Finally, we discuss the current challenges and future perspectives for the development of self-assembling GF-mimetic peptide systems in regenerative medicine.
Chronic low-grade inflammation (CLGI) contributes to several skeletal muscle disorders as sarcopenia, still lacking disease-specific therapies. Palmitoylethanolamide (PEA) is a natural anti-inflammatory mediator with proven safety, but its high lipophilicity and poor solubility limit bioavailability and muscle delivery. The intrinsic difficulty of actively targeting skeletal muscle cells further supports the need for biomaterial-based strategies to enhance PEA delivery and therapeutic potential. Here, solid lipid nanoparticles (SLNs) and hybrid polymer-lipid PLGA nanoparticles (hyPLGA) are directly compared to identify a nanocarrier optimized for PEA delivery and bioactivity in skeletal muscle tissue. Both carriers exhibited favorable physicochemical profiles and maintained dimensional features after lyophilization, with PEA-SLNs achieving higher encapsulation efficiency. Despite this, PEA-hyPLGA nanoparticles demonstrated superior functional performance in vitro. In C2C12 myoblasts, both formulations were internalized efficiently, yet PEA-hyPLGA nanoparticles exhibited faster uptake kinetic. Notably, PEA-hyPLGA significantly reduced IL-6 and TNF-α transcript levels, enhanced PPAR-α nuclear localization, and mitigated LPS-induced cytotoxicity more effectively than Native PEA or PEA-SLNs. The efficient internalization of PEA-hyPLGA nanoparticles was also observed in human 3D muscle constructs, where the nanoparticles exhibited the ability to penetrate differentiated myofibers. Their behavior was further validated in vivo, where a prolonged retention of PEA-hyPLGA nanoparticles and their ability to reduce inflammatory markers in mouse skeletal muscle, upon intramuscular injection, was observed. Altogether, these findings indicate that hyPLGA nanoparticles represent a convenient nanostructure platform for PEA delivery and anti-inflammatory function in skeletal muscle, supporting their envisaged use as systemic administered targeted therapy toward translational strategies for sarcopenia.
The treatment of malignancies remains a formidable challenge, driven by the complex interplay of exosome-mediated metastasis and PD-L1-driven immune evasion. Overcoming these barriers through simultaneous modulation of both pathways represents a critical, yet unmet, need in cancer therapy. To address this, we engineer a supramolecular lipid nanoparticle (LNP) wherein lipid-modified cyclodextrin and oxaliplatin (OxPt-2PA) synergize as both a delivery vector and an immunogenic cell death inducer. Leveraging multiple supramolecular interactions, this platform co-encapsulates the exosome inhibitor Nexinhib20 and small interfering RNA targeting PD-L1 (siPD-L1), orchestrating a multi-pronged attack on tumor progression and immunosuppression. In vivo, this therapeutic strategy markedly enhances dendritic cell maturation, promotes cytotoxic T cell infiltration and significantly suppresses both primary tumor growth and distant metastasis. This work establishes a chemotherapy-induced supramolecular integrated co-delivery platform that simultaneously counteracts metastasis and immunosuppression via "drug-and-gene" therapy, offering a promising strategy for the treatment of aggressive cancer.
Clinical management of acute corneal alkali burns is limited by tear washout and the failure of monotherapies to break the inflammation-neovascularization cycle. To address this, we developed a thermosensitive hydrogel (PRP/QR@gel) co-loaded with platelet-rich plasma (PRP) and quercetin (QR). The low-viscosity precursor adaptively fills irregular defects and solidifies around ocular surface temperature, establishing a tear-resistant drug depot. Mechanistically, the rapid release of hydrophilic PRP drives ordered corneal remodeling via the PI3K/Akt/mTOR pathway. Concurrently, the sustained release of hydrophobic QR scavenges ROS, suppresses NF-κB-mediated inflammation, and blocks HIF-1α/VEGF-driven pathological neovascularization. In a rabbit alkali burn model, PRP/QR@gel accelerated complete epithelialization within 7 days and reduced clinical opacity scores by 50%. This in situ-forming hydrogel offers a translatable solution for severe ocular chemical injuries.
Ferroptosis therapy holds great potential in metastatic cancer treatment. Whereas, Dickkopf-related protein-1 (DKK1) that highly expressed in various tumors might contribute to low ferroptosis sensitivity of tumor cells, which imposed restrictions on ferroptosis therapy. Our research revealed that DKK1 inhibition could sensitive tumor cells to ferroptosis by obstructing the cystine-GSH-GPX4 axis and the CoQ10-FSP1 axis. Moreover, DKK1 inhibition facilitated dormancy of tumor cells, thereby inhibiting their metastatic proliferation. Encouraged by that, a strategy combining DKK1 inhibition with ferroptosis induction was innovatively proposed for metastatic cancer treatment. And a sulfated hyaluronic acid (SHA)-functionalized liposome co-encapsulating DKK1 inhibitor (Gallocyanine) and ferroptosis inducer (RSL3) was developed for this purpose. The constructed SLip/G+R simultaneously targeted primary tumors, circulating tumor cells and tumor metastases by not only binding to P-selectin/CD44 on tumor cells, but also hitchhiking on activated platelets with tumor cells tendency. Particularly, SLip/G+R increased P-selectin/CD44 on tumor cells through DKK1 inhibition, providing more targets for itself and enhancing the targeting effect in a "self-promoting" manner. Due to the self-promoting ferroptosis amplification, SLip/G+R exerted excellent anti-tumor and anti-metastasis efficacy. Overall, this study provided a new idea for efficiently eliminating metastatic tumor cells. It is conducive to promoting the development of ferroptosis therapy, and is of great significance for metastatic cancer treatment.
Bacterial biofilms and persistent inflammation undermine conventional antibiotic therapy for gastrointestinal infections, necessitating integrated therapeutic strategies. Here, we develop a nitric oxide (NO)-entrapping coacervate foam (LA-CHSF-NO) from α-lipoic acid-grafted chitosan and sodium alginate that synergistically combines antimicrobial, antioxidant, anti-inflammatory, and mucosal-healing functions. The foam exhibits robust mechanical properties (storage modulus ∼1184 Pa), shear-thinning injectability, self-healing capacity, and sustained NO release over 4 h, enabling durable mucosal retention. LA-CHSF-NO achieves potent bactericidal and anti-biofilm activity against E. coli, MRSA, and P. aeruginosa (>85% eradication) through synergistic membrane disruption and NO-mediated nitrosative stress. Mechanistically, the foam scavenges ROS, activates the Keap1-Nrf2-HO-1 antioxidant axis, promotes macrophage M2 polarization, and suppresses TNF-α, IL-6, and IL-1β while restoring IL-10. In DSS-induced colitis, LA-CHSF-NO alleviates disease severity, repairs epithelial barrier via upregulating occludin, ZO-1, and claudin-5, restores antioxidant enzymes, and normalizes gut microbiota. Remarkably, in H. pylori-induced gastritis, oral LA-CHSF-NO achieves superior bacterial clearance and mucosal healing versus standard triple therapy. This gas-delivery platform offers a paradigm-shifting approach for combating antibiotic-resistant gastrointestinal infections and chronic inflammatory diseases.
Lyotropic liquid crystals (LLCs) are a promising class of self-assembled systems with highly tunable topologies. They offer considerable potential for long-acting drug delivery because of their sustained-release capabilities and facile preparation. However, molecular mechanisms underlying LLC formation and the effects of topology on drug release remain poorly understood. In this study, LLC systems with distinct topologies were constructed using soya phosphatidylcholine and glyceryl dioleate. The release behaviors of three model compounds with different hydrophilicities were systematically investigated through in vitro and in vivo experiments. Additionally, molecular dynamics simulations were employed to visualize the lipid self-assembly and elucidate drug release mechanisms at the molecular level. The results reveal that drug release is synergistically regulated by the LLC structure and intermolecular interactions between drugs and lipids (soya phosphatidylcholine and glyceryl dioleate). Notably, molecular dynamics simulations provide ultramicroscopic insights into LLC formation and drug release mechanisms, complementing experimental observations and offering perspectives that are difficult to achieve using conventional techniques.
Efficient movement of lipid molecules across multiple cell layers is a fundamental requirement for lipid-based drug delivery, but the physicochemical and molecular properties that enable this process remain poorly understood. To address this question, we generated a library of lipids with the fluorescent cyanine 3 and cyanine 5 dye headgroups, different tail lengths, and headgroup-tail linkers. We used multicellular 3D breast cancer spheroids to study the lipid penetration into the core (core/periphery ratio) with confocal microscopy. The parent non-lipid dye showed complete penetration into the core of spheroids. Short-chain (C12) lipids with stable linkers were distributed throughout the spheroids and reached the core, whereas long-chain (C18) lipids with stable linkers accumulated predominantly at the periphery. On the other hand, ester-based lipids underwent serum-mediated hydrolysis and the release of low-molecular-weight dye that showed deep spheroid penetration. Increasing the solubility and reducing the aggregation of C18 lipids via co-formulation with DSPE-PEG2000 dramatically enhanced migration and penetration into the core. The same principles are applicable to glioma spheroids, patient-derived glioma spheres, human midbrain organoids, and human patient glioma. Mechanistically, the migration and penetration of lipid molecules through multicellular layers is facilitated by increased lipid solubility and by decreased self-assembly. This work outlines key principles for designing lipid-based probes and therapeutics for effective tumor and tissue distribution.
Drug delivery to the CNS has traditionally been evaluated by the ability of carriers to cross the blood-brain barrier (BBB). This barrier-centric view has enabled important progress, but it overlooks a therapeutically significant and design-relevant feature of the neurovascular unit: cerebral endothelial cells and pericytes are active regulators of barrier integrity, vascular tone, immune trafficking, amyloid clearance, and perivascular remodeling. In many neurological disorders, the vascular interface is therefore not merely an obstacle to drug access but also part of the pathological process. This review introduces a vascular-interface-guided framework for CNS delivery system design. We discuss how disease-associated vascular phenotypes, including barrier disruption, immune-endothelial activation, vascular-tone dysregulation, and extracellular-matrix/basal-lamina remodeling, define distinct therapeutic entry points at the luminal endothelial surface, within endothelial trafficking pathways, or in the perivascular niche. We further discuss how receptor identity, ligand affinity and valency, particle size, geometry, surface chemistry, and intracellular sorting determine whether nanocarriers undergo transcytosis, recycling, lysosomal degradation, or endothelial retention. Particular emphasis is placed on endothelial-pericyte crosstalk, pericyte-directed delivery, perivascular depot formation, safety constraints, and translational model selection. Finally, we highlight how computational and predictive modeling could help determine when retention-oriented designs should be prioritized over transcytosis-oriented strategies. We propose that next-generation CNS nanomedicines should be designed by considering therapeutic action at luminal, endothelial, and perivascular sites according to the vascular state of disease, rather than being guided solely by parenchymal delivery.
This study introduces a versatile platform for targeted drug delivery that addresses the complexities of conventional immunoliposome preparation. Traditional methods for conjugating a monoclonal antibody (mAb) to the surface of liposomes require target-specific chemical modification for each antibody, frequently resulting in suboptimal ligand orientation, steric hindrance of the antigen-binding sites, and a profound lack of modularity across different targeting systems. We developed Universal Particles (UPs), which are liposomal nanocarriers displaying high-affinity secondary antibodies on their surface. This design enables rapid, non-covalent functionalization by instantly binding to the constant (Fc) region of any whole-molecule primary targeting antibody without the need for chemical modification, thereby promoting a highly accessible, outward-facing display of the antigen-binding domains. In vitro experiments confirmed that UPs successfully functionalized with primary antibodies, leading to specific molecular recognition and enhancing cellular uptake of anti-Muc1/Muc4 UPs by Panc02 pancreatic cancer cells. Analytical flow cytometry confirmed the high expression of these target antigens in the Panc02 line, with 99.5% of cells expressing Muc1 and 99.9% expressing Muc4. In vivo biodistribution studies validated the platform's versatility: αCD31 UPs showed increased accumulation in the lungs, while dual anti-Muc1/Muc4 UPs demonstrated significantly enhanced tumor accumulation in a murine pancreatic tumor model compared with untargeted controls. The UP platform offers a simple approach for antibody-based liposomal targeting, providing a foundation for targeted delivery systems aimed at enhancing therapeutic selectivity and reducing off-target effects in preclinical models.
mRNA vaccines have made substantial clinical advances, yet their full clinical potential can be further expanded by enhancing cytosolic delivery. Here, we integrate a nitric oxide (NO) generator with lipid nanoparticles (LNPs) to boost mRNA delivery efficiency and mRNA-based vaccine efficacy. SM-102/DEA LNPs, the lead formulation, achieved significantly higher mRNA delivery compared with the FDA approved SM-102 LNPs in both cellular and animal models. The intramuscular administration of SM-102/DEA LNPs encapsulating mRNA encoding SARS-CoV-2 spike protein elicited substantially higher anti-spike IgG levels and robust CD8+ and CD4+ T cell responses compared to SM-102 LNPs. Mechanistic studies revealed that DEA incorporation promotes endosomal escape of mRNA cargos in SM-102/DEA LNPs. These findings establish NO-assisted LNPs as a unique platform for potent mRNA delivery, which provides a new paradigm for overcoming endosomal barriers and improving the efficacy of mRNA vaccines.
Natural killer (NK) cells play a pivotal role in innate immunity, effectively eliminating tumor cells. However, their therapeutic potential in solid tumors is limited due to challenges such as limited infiltration, poor persistence, and functional exhaustion. To address this, NK92 cells are empowered with micro-armory (MA) of interleukin 15 (IL15) and subsequently encased in an injectable supramolecular hydrogel based on hydroxypropyl methylcellulose-nanoparticle interactions. The biocompatible hydrogel serves as a locoregional depot for engineered NK92 cells and confers sustained release. Owing to ambient release of IL15, MA backpacking to NK cell surface assists in situ maintenance in cell survival, activation, and cytotoxicity. In a mouse model of subcutaneous 4T1 breast cancer, the biohybrid extends the localized retention of NK92 cells to at least 15 days, enhances tumor infiltration and facilitates localized intra-tumoral distribution of IL15, thereby potently inhibiting tumor growth. In ex vivo model of human breast cancer tissues, engineered NK92 cells demonstrate superior functionality and further re-activate cytotoxic T cells by delivering IL15, consistently augmenting anti-tumor efficacy. The strategy integrating surface-engineered NK cells and localized hydrogel enables persistently in situ cell activation and subsequent intra-tumoral immune reinvigoration, disclosing clinically translational potential for solid tumor therapy.
Excessive oxidative stress and neuroinflammation caused by retinal detachment (RD) drive progressive photoreceptor degeneration, posing a major challenge to functional vision recovery even after successful anatomical reattachment. These limitations highlight the urgent need for alternative or adjunctive therapeutic strategies to protect photoreceptors. Here, smart supramolecular Cerium-Rutin nanoparticles (CRNPs) are developed for coordinated redox and immunomodulatory therapy in RD. CRNPs are constructed through the coordination assembly of cerium ions with the natural flavonoid Rutin, integrating the reversible Ce3+/Ce4+ redox-switching capacity with the intrinsic anti-inflammatory activity of Rutin. This supramolecular nanozyme platform enables dynamic regulation of oxidative and inflammatory homeostasis within the injured retina. In vitro, CRNPs protect microglial and photoreceptor cells by scavenging reactive oxygen species (ROS) and suppressing inflammatory activation, demonstrating both anti-inflammatory and cytoprotective effects. In vivo, CRNPs effectively preserve photoreceptor morphology, protect outer nuclear layer integrity, enhance retinal electrophysiological responses and vision function in an RD model. Mechanistically, CRNPs first mitigate oxidative stress, which in turn suppresses activation of the NLRP3/ASC/caspase-1 signaling pathway, thereby reducing pro-inflammatory microglial activation and limiting the release of inflammatory mediators. Collectively, this study establishes a redox-active nanozyme platform capable of restoring retinal homeostasis and mitigating neuroinflammation, providing a promising nanotherapeutic approach for the treatment of RD and other oxidative stress-associated neurodegenerative diseases.
Antibody-drug conjugates (ADCs) are now established approaches to the development of precision-guided therapeutics, yet some of the clinical translation effort has been constrained by a paradox at the heart of their design, that is the most effective cytotoxic payloads are also among the most hydrophobic. This intrinsic physicochemical mismatch - between a hydrophilic biological carrier and a hydrophobic small-molecule payload - continues to challenge the stability, pharmacokinetics, and therapeutic index of ADCs. Incorporation of hydrophilic linker architectures has therefore emerged as a critical strategy to counterbalance payload-associated hydrophobicity and enhance overall biophysical and biological performance. Here we examine these approaches within a systematically organized and conceptually unified framework that categorizes hydrophilic linker design according to the strategic placement of solubilizing elements along the linker-payload continuum, as illustrated in Fig. 1. Specifically, potential sites for hydrophilic group incorporation - listed in order of increasing distance from the antibody - include the antibody attachment region, the linker spacer, and the payload release site. Each section of the review surveys representative literature examples within one of these spatial domains, highlighting both established and emerging design principles and elucidating key structure-function relationships governing ADC stability, pharmacokinetics, and controlled payload release. Major classes of hydrophilic motifs, including polyethylene glycol (PEG) chains, zwitterionic structures, carbohydrate-based moieties, and next-generation water-solubilizing scaffolds, will be discussed in a comparative manner. We will also demonstrate how we conceive our internally developed patented hydrophilic linker architecture as an illustration for potential future directions. STATEMENT OF SIGNIFICANCE: We reviewed the principles of ADCs linkers and shared our perspectives on the challenges and innovative approaches to the future ADC drug development.
Enhancing the safety and efficacy of systemically administered oncolytic adenoviruses remains a significant challenge to achieve effective targeting of primary tumors and disseminated disease. Intravenous administration exposes viral particles to various blood components interfering with their therapeutic activity. To protect adenoviruses from the inactivating factors we developed a shielding strategy based on a nanoparticle formulation reactive to a specific-site in the hexon hypervariable region 1. We propose a novel coating approach based on the combination of a bioresponsive oligopeptide-modified poly(β-aminoester)s (OM-PBAE-CRRR) and an irreversible linear PEG polymer with protruding ends to shield the oncolytic adenovirus AdNuPARc-E (PEPB). The formulated virus displays a slight delay in the transduction and replicative capacity at early time points that normalizes in a few days. Interestingly, similar oncolytic efficacy to the naked virus was observed in vitro, with enhanced antitumor effect in vivo in a pancreatic cancer model. In accordance, PEPB showed significantly enhanced pharmacokinetics and increased liver and tumor transduction in the xenograft model. In the presence of neutralizing antibodies (NAbs) coated viral particles maintained the infectivity and the replication capacity. Notably, in pre-immunized immunocompetent mice, protection from NAbs resulted in a higher viral accumulation in tumors than in the liver and was associated with significant antitumor activity. In summary, our findings indicate that the proposed formulation PEPB -the oncolytic adenovirus AdNuPARc-E site-specifically shielded with OM-PBAE-CRRR/PEG - offers a promising approach to improve tumor targeting after systemic administration, even in the presence of pre-existing neutralizing antibodies.
Acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory disease with a high mortality rate. Conventional in vivo monocyte-targeted strategies are fundamentally limited by the low physiological abundance of circulating monocytes, which represents a major unmet technical barrier on delivery efficiency. Herein, we report an organ-to-cell cascade-targeting strategy that overcomes this long-standing barrier via in situ monocyte recruitment in the pulmonary microvasculature. Herein, we engineered mMP-DDAB, a methylprednisolone (MPS)-loaded liposome co-modified with the lung-targeting functional lipid and CCR2-binding peptide. By virtue of DDAB-mediated lung retention and MP-triggered chemotaxis, mMP-DDAB first accumulates in the pulmonary microvasculature, then actively recruits monocytes, achieving an organ-to-cell cascade-targeting delivery. Following monocyte-targeted delivery and sustained MPS release, mMP-DDAB exerted potent anti-inflammatory and pro-resolving effects in the LPS-induced ARDS mouse model, as evidenced by reduced BALF neutrophil infiltration and protein leakage, suppressed pro-inflammatory cytokines, modulated the pulmonary monocyte/macrophage activation profile toward a more pro-resolving state, and mitigated histopathological lung injury.
Dry eye syndrome (DED), a multifactorial ocular surface disorder, presents significant treatment challenges in severe cases where conventional eye drops demonstrate limited efficacy. Current lacrimal occlusion strategies, while clinically valuable, are compromised by a device migration and sizing inaccuracies that undermine therapeutic reliability. To address these limitations, we engineered an innovative SwitchPlug hydrogel as a switchable punctal plug formed in situ from pre-assembled mPEG-PLGA nanoparticles under the morphological and thermal cues of the lacrimal canaliculus, which affords reversible punctal occlusion and broad-spectrum drug loading capacity. The SwitchPlug hydrogel exhibits rapid sol-gel transition at physiological canalicular temperature (∼37 °C), forming stable occlusions that significantly prolong tear retention while permitting gentle, cooling-induced liquefaction for atraumatic removal, a critical safety advantage over current plugs. Beyond its mechanical occlusion, this smart hydrogel functions as a versatile drug reservoir capable of sustained release across diverse therapeutics, including hydrophobic small molecules (e.g., cyclosporine A), hydrophilic compounds (e.g., dequafosil sodium), and macromolecular proteins (e.g., human epidermal growth factor). In both mouse and rabbit DED models, cyclosporine A-loaded SwitchPlug hydrogel (CsA@SwitchPlug) demonstrated superior therapeutic efficacy compared to commercial formulations, effectively restoring tear secretion, suppressing corneal inflammation, reducing epithelial apoptosis, and accelerating tissue repair. Comprehensive biosafety evaluation confirmed excellent ocular and systemic biocompatibility. This integrated platform represents a paradigm shift in DED management by simultaneously addressing three critical clinical needs, including prolonged ocular retention, customizable drug delivery, and reversible mechanical occlusion, offering new possibilities for personalized and combinatorial therapy of DED.
