Dermal substitutes that simultaneously provide structural fidelity and bioactive signaling remain limited in clinical wound care. Here, we report a hybrid dermal patch based on decellularized bovine dermis (dDerm) coated with photo-crosslinked methacrylated hyaluronic acid (MeHA-Derm). Successful functionalization was confirmed by FTIR and SEM, demonstrating formation of a uniform hydrogel layer. The MeHA-Derm patches exhibited enhanced swelling capacity and improved mechanical performance, with Young's modulus significantly increasing relative to native bovine skin. HaCaT keratinocytes cultured on MeHA-Derm showed high cytocompatibility, with viability exceeding 90% at days 3 and 5. Metabolic activity was significantly elevated in MeHA-Derm compared to dDerm. Immunofluorescence revealed increased vinculin secretion, indicating stronger focal adhesion. In vitro scratch assay demonstrated a significantly accelerated wound closure of 82 ± 12% on day 5 on MeHA-Derm versus dDerm at 43 ± 25%. Moreover, ex vivo analysis confirmed superior gap closure, reaching 92 ± 4% by day 10 compared to 84 ± 14% on dDerm. Overall, the MeHA coating enhances hydration, mechanical stability, and cell-matrix interactions while preserving native dermal architecture. This strategy provides a scalable and biologically instructive platform for next-generation skin regeneration and advanced wound care applications.

Multiple sclerosis (MS) is an autoimmune disease currently being treated with broad immunosuppressive drugs. However, antigen-specific therapies offer a strategy to selectively reestablish self-tolerance within the autoreactive T cell compartment with fewer side effects. Polymeric microparticles are an effective platform for encapsulating disease-relevant antigens to achieve antigen-specific T cell tolerance via uptake by antigen-presenting cells (APCs). For this purpose, the most commonly targeted APCs are dendritic cells (DCs). However, B cells also present antigen and have demonstrated therapeutic efficacy in MS when targeted by depleting anti-CD20 antibodies. Microparticles comprised of the polymer acetalated dextran (Ace-DEX) bind to B cells more efficiently than other biomaterial systems and reside at the surface without internalization due to microparticle size. In this work, we systematically varied Ace-DEX parameters, including the fabrication method, molecular weight, hydrophobicity, and acetal exposure to understand the relationship between these properties and microparticle binding to B cells. These features strongly influenced B cell association, highlighting the sensitivity of immune recognition to polymer chemistry. The Ace-DEX MPs (AMPs) were evaluated in a preclinical MS model (experimental autoimmune encephalomyelitis (EAE)) using an adoptive transfer of ex vivo B cells surface decorated with MOG35-55 loaded AMPs and achieved a significant decrease in the clinical score. This work demonstrates the role of polymer properties in B cell binding and outcomes as an antigen-specific therapeutic vaccine.

Chronic inflammation at the implant-tissue interface is a major contributor to implant failure. Therefore, enhancing the biological response of titanium (Ti) surfaces is critical for promoting early osseointegration and improving long-term implant stability. In this study, alkali-heat-treated (AHT) Ti was evaluated as a platform for the controlled delivery of curcumin (Cur), a natural anti-inflammatory compound. The release kinetics of curcumin and the interactions between curcumin-loaded AHT Ti surfaces and RAW264.7 macrophages were investigated in vitro. Various polymer coating strategies were applied to modulate curcumin release. The presence of poly(lactic-co-glycolic acid) (PLGA) reduced the curcumin release under both physiological (pH 7.4) and acidic (pH 5.0) conditions, with uncoated AHT samples exhibiting the greatest cumulative release (∼21.3 μg) in Study 1. Increasing the loaded curcumin amount from 100 to 300 μg resulted in a decrease in the release for both pH 7.4 and pH 5.0, whereas the incorporation of polyethylene glycol/polycaprolactone (PEG/PCL) coating enhanced the gradual curcumin release (Study 2). Increasing the curcumin loading from 50 to 100 and 300 μg increased the total amount of curcumin released, with the 300 μg group exhibiting a more gradual release profile. However, the percentage of curcumin released decreased as the loading amount increased (Study 3). When macrophages were cultured on Ti surfaces, AHT samples exhibited higher cell viability than polished (P) control samples, and the presence of curcumin reduced cell viability in a dose-dependent manner. While macrophages cultured on AHT surfaces exhibited a transient increase in pro-inflammatory marker expression at 24 h compared with polished surfaces, the expression of these markers was reduced by 48 h. Notably, curcumin significantly decreased pro-inflammatory cytokine expression at both the gene and protein levels and suppressed NF-κB activation in macrophages exposed to inflammatory stimuli. Overall, the sustained and controlled release of curcumin from AHT Ti surface is highly dependent on the curcumin loading amount as well as the presence and composition of the polymer coating. Moreover, both AHT and curcumin significantly reduced inflammatory responses in macrophages, demonstrating the potential of the curcumin-loaded AHT Ti platform as an immunomodulatory surface for improving the biological performance and long-term success of Ti implants.

Poly(lactic-co-glycolic acid) (PLGA) scaffolds are widely utilized in tissue engineering for their biodegradability and mechanical robustness; however, their inherent hydrophobicity and bioinert nature often result in poor initial cell attachment, a critical bottleneck for stable tissue integration. In this study, we developed a modular dual-layer surface functionalization strategy that combines a poly-L-lysine (PLL) electrostatic priming layer with a recombinant elastin-like polypeptide featuring RGD and YIGSR motifs (RY-ELP). The sequential PLL/RY-ELP coating significantly enhanced surface wettability without compromising the scaffold's interconnected porous architecture. This bioactive interface supported robust early adhesion and survival of both HEK293 cells (as a model for weak adherence) and human dental pulp stem cells (hDPSCs). Mechanistically, this enhanced interaction was accompanied by the rapid activation of focal adhesion-related signaling pathways, including FAK, paxillin, and ERK, alongside the upregulated expression of integrin β1 and vinculin. Beyond initial survival, the PLL/RY-ELP coating effectively promoted the osteogenic differentiation of hDPSCs, as evidenced by increased osteogenic marker expression (RUNX2, COL1A1, ALPL, SP7, and BGLAP) and superior matrix mineralization. These findings demonstrate that combining electrostatic priming with sequence-defined bioactive motifs offers a versatile and effective approach to overcome the biological limitations of PLGA scaffolds for regenerative medicine.

Chronic endometritis (CE) is a persistent inflammatory disorder of the endometrium characterized by aberrant plasma cell infiltration and strongly associated with female infertility. CE pathogenesis is driven by persistent microbial stimulation, excessive reactive oxygen species (ROS) accumulation, and local immune dysregulation, whereas antibiotics and hysteroscopic surgery do not sufficiently resolve the sustained oxidative-inflammatory microenvironment. A sprayable antioxidant powder, RuO2@GelMA@TA-Fe[3+] (RGTF), is developed for localized remodeling of endometrial oxidative-inflammatory homeostasis. A tannic acid-Fe[3+] metal-phenolic network (MPN) serves as a functional interfacial layer, providing wet-tissue adhesion, prolonged local retention, and complementary free-radical scavenging, while embedded RuO2 nanozymes enable efficient ROS elimination. Optimized RGTF exhibits favorable sprayability, hydration-triggered tissue adhesion, and robust scavenging activity against hydrogen peroxide (H2O2) and multiple representative free radicals. In vitro, RGTF reduces intracellular ROS in H2O2-stimulated human endometrial stromal cells (HESCs) and promotes macrophage transition from a pro-inflammatory to a reparative phenotype. In a lipopolysaccharide (LPS)-induced rat CE model, local RGTF treatment alleviates oxidative damage and inflammation, promotes endometrial structural restoration, and rescues fertility-related dysfunction. This MPN-enabled platform provides a promising local strategy for CE intervention.

Effective treatment for malignant tumors continues to represent an urgent unmet clinical need. Triple-negative breast cancer (TNBC) constitutes a therapeutic challenge on account of its aggressive nature and limited response to conventional therapies. Radiotherapy serves as a cornerstone for cervical cancer treatment. Nevertheless, radioresistance frequently gives rise to therapeutic failure in cervical cancer. We developed ultrasmall, pH-responsive DNA@WO3-x nanodots to enhance the accumulation of nanodots within tumors, thereby improving therapeutic efficacy. The nanodots undergo intelligent self-assembly within the acidic tumor microenvironment, leading to enhanced accumulation and retention. DNA@WO3-x functions dually as an effective computed tomography (CT) contrast agent for tumor visualization and a potent radiosensitizer. The high-Z element tungsten and remarkable photothermal conversion capability in the NIR-II window enable synergistic radio-photothermal therapy (RT-PTT). In vitro and in vivo studies demonstrated that the combined treatment via single-nanodot triple-therapeutic effects potently suppresses the growth of tumor cells. Consequently, this synergistic strategy achieved remarkable inhibition of primary tumor growth and suppression of distant metastasis in orthotopic TNBC models, with no significant systemic toxicity observed. Furthermore, in vitro validation experiments verified that the developed nanodots can effectively sensitize cervical cancer cells to radiotherapy, thereby achieving prominent anti-tumor therapeutic effects. This work presents a versatile and integrated theranostic strategy that realizes potent tumor suppression via single-nanodot triple-therapeutic effects, offering a promising approach for the precise and effective treatment of aggressive solid tumors.

Enhancing tumor accumulation after systemic administration while minimizing off-target hepatic deposition remains a major challenge for effective cancer therapy. Herein, we developed a "prime-and-hitch" two-step nanoplatform strategy to address this issue. A PEGylated Ce6 prodrug (CPD) was administered via a single low-dose intratumoral injection, enabling sustained intratumor retention for up to 10 days. Laser irradiation induced a temporally controlled acute inflammatory response, with inflammatory cytokines and neutrophil infiltration peaking at 1 h. In this optimal window, an acidic tumor microenvironment-responsive PEGylated gossypol prodrug functionalized with an anti-Ly6G antibody (αLy6G-pGPD) was intravenously injected to enable binding to circulating neutrophils via Ly6G-specific recognition, thereby achieving neutrophil "hitchhiking"-mediated active tumor targeting. Copper ions (Cu[2+]) were subsequently coordinated to generate αLy6G-pGPD@Cu, enabling the combined induction of tumor cuproptosis and M1 polarization of tumor-associated macrophages (TAMs). In vivo, the combination of a single low dose CPD administration with repeated laser irradiation and αLy6G-pGPD@Cu treatment markedly suppressed 4T1 tumor growth while increasing the infiltration of cytotoxic T lymphocytes (CTLs) and M1-polarized TAMs within the tumor microenvironment. Collectively, this single low-dose, multiple irradiation-mediated neutrophil hitchhiking strategy provides a robust and versatile platform for extrahepatic targeting delivery and enhanced tumor accumulation of nanotherapeutics.

In the regulatory science of absorbable medical devices, traditional in vivo degradation evaluations are often hindered by lengthy evaluation cycles and ambiguous standards. This restricts the research, development, and translation of novel embolic materials. The lack of an evaluation system to determine whether tissue responses have reached a "degradation steady-state endpoint" is particularly critical. This study systematically evaluated the biological efficacy and in vivo degradation steady state of a composite temperature-sensitive embolic agent based on sodium alginate and poloxamer. This gel undergoes a spontaneous phase transition at body temperature. Combined with a dual-lumen microcatheter delivery technique, it achieves instant crosslinking with calcium ions, exhibiting excellent resistance to blood flow washout. The embolization results in canine hepatic and renal artery models and rabbit renal tumor in situ models confirmed the efficacy of this composite gel as a tumor embolic agent. Its ability to induce coagulation necrosis and apoptosis in tumor tissues outperformed current clinical lipiodol and polyvinyl alcohol (PVA) microspheres. A six-month porcine hepatic/renal artery study examined residual implant-like material, recanalization, local histopathology, selected endothelial markers, and systemic observations. Under the tested protocols, the PS gel occluded target vessels and showed good biological safety. In pigs, implant-like material remained at six months, while selected histological injury and inflammatory measures were lower than at earlier terminal time points. Histopathological results indicated that local macrophage phagocytosis and inflammatory responses in the target vessels were active between 1 and 3 months. By 6 months, the inflammation level had significantly subsided to a mild state, with concurrent reductions in fibrosis and fatty infiltration. This was accompanied by prominent tissue repair and remodeling, marking a smooth transition of the tissue response toward a steady state. The results support a candidate criteria-based framework for future prospective evaluation. The results justify further formulation characterization, controlled long-term studies, and component-resolved degradation analysis.

Oral leukoplakia (OLK) is a prevalent oral potentially malignant disorder. Targeting the core pathogenesis of OLK, we herein develop a poly(lipoic acid)-based bioadhesive elastomeric patch via a one-step solvent evaporation strategy by integrating lipoic acid with lauroyl arginate ethyl ester hydrochloride, an FDA-approved antimicrobial agent. In this binary system, LAE self-assembles into nanomicelles with outwardly radiating guanidino groups acting as "multi-armed grippers" that suppress room-temperature depolymerization of PolyLA through multiple hydrogen bonds and electrostatic interactions with carboxyl groups. The abundant carboxyl groups on the elastomer surface provide excellent wet tissue adhesion suitable for the dynamic oral environment. Surfactants with distinct terminal groups are further applied to validate the universality of this binary design strategy and to clarify the regulatory effects of intermolecular interaction strength on material stability, crystallinity and mechanical performance. In vitro biological evaluations demonstrate that the PolyLA/LAE patch can efficiently scavenge ROS, inhibit C. albicans proliferation, and induce apoptosis of dysplastic oral keratinocytes, while maintaining favorable biocompatibility. In a rat OLK model, the patch exhibits satisfactory therapeutic outcomes that are comparable to clinical vitamin A ointment. Collectively, this binary synergistic elastomeric patch offers a simple and universal strategy for treating refractory oral mucosal lesions represented by oral leukoplakia.

Lung cancer remains one of the most prevalent and lethal malignancies worldwide, with its clinical management being hindered by high invasiveness, early metastasis, therapeutic resistance, and the severe adverse effects associated with conventional treatment modalities. Nanoparticle-based formulations have emerged as promising platforms for lung cancer therapy owing to their ability to enhance drug bioavailability and enable targeted, sustained, and controlled drug delivery. Despite these advantages, their broader clinical applications are often limited by insufficient stability, rapid systemic clearance, and suboptimal targeting efficiency in complex physiological environments. In this context, zeolitic imidazolate frameworks (ZIFs), a distinctive subclass of metal-organic frameworks, have attracted considerable attention because of their high surface area, tunable pore structures, excellent loading capacity, biocompatibility, and stimulus-responsive degradation behaviour. These unique features enable the efficient encapsulation of therapeutic and diagnostic agents and facilitate their controlled release within the tumor microenvironment, thereby improving treatment specificity and reducing off-target effects. This review discusses the fundamental design principles, synthesis strategies, structural characteristics, and functionalization approaches of ZIF-based materials, with particular emphasis on their emerging applications in lung cancer diagnosis and therapy. Recent advances in biosensing, bioimaging, drug delivery, chemotherapy, phototherapy, immunotherapy, and multifunctional therapeutic platforms are critically examined, together with the interactions of ZIF-based systems with the tumor microenvironment. The review further highlights the growing role of artificial intelligence in the screening, design, and optimization of ZIF materials and discusses the major challenges associated with their clinical translation. Collectively, these advances underscore the considerable potential of ZIF-based platforms in developing more effective and safer strategies for lung cancer diagnosis and therapy.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and irreversible joint damage. Iguratimod (IGU), a novel small-molecule disease-modifying antirheumatic drug (DMARD), is limited by low solubility, inadequate joint accumulation and hepatotoxicity when administered orally. To address these limitations, we developed an injectable composite hydrogel (IGU-Man-Lip@Vc-HA) by incorporating mannose-modified IGU liposomes (IGU-Man-Lip) into a vitamin C-functionalized hyaluronic acid (Vc-HA) matrix with ROS-scavenging activity. In this system, IGU-Man-Lip overcame the poor solubility of iguratimod and actively targeted synovial macrophages via overexpressed mannose receptors (MR), thereby downregulating inflammatory cytokine levels and exerting bone-protective effects. Concurrently, the Vc-HA hydrogel scavenged ROS to remodel the inflammatory microenvironment. Furthermore, the resistance of Vc-HA to degradation significantly prolonged intra-articular retention, thereby enhancing drug accumulation in joints. This hybrid delivery system exhibited favorable biocompatibility, as well as potent anti-inflammatory and bone-protective efficacy. In collagen-induced arthritis (CIA) rats, intra-articular injections achieved significant joint enrichment, potent anti-inflammatory activity and articular repair without detectable systemic toxicity. This multifunctional composite system constitutes a synergistic RA therapeutic strategy by concurrently addressing targeted drug delivery and oxidative stress to improve anti-inflammatory efficacy along with bone protective effects, providing a promising RA-specific treatment approach.

The repair of long-gap peripheral nerve defects remains challenging, as regeneration depends on temporally coordinated bioactive regulation and spatially organized guidance. To address this, we developed a spatiotemporally coordinated nerve conduit integrating an injectable thermosensitive poly(amino acid) hydrogel with an aligned-random bilayer poly(ε-caprolactone) (PCL) wall. A brain-derived neurotrophic factor (BDNF)-mimetic RGI peptide was covalently tethered to mPEG-PMet-PLysMA (P), and retinoic acid (RA) was physically incorporated to form P-RGI@RA. Aligned luminal fibers promoted Schwann cell orientation and spreading, whereas random outer fibers increased transverse tensile strength and elastic modulus by 4.4- and 6.0-fold, respectively, relative to fully aligned membranes. In vitro, the RGI-conjugated formulation increased the mean longest neurite length in PC12 cells, whereas the RA-containing formulation enhanced Schwann cell migration, with the respective responses reaching 1.9- and 1.7-fold the control values. In a 10 mm rat sciatic nerve defect model, P-RGI@RA-filled conduits produced the most favorable repair profile among conduit-treated groups. At 12 weeks, the compound muscle action potential (CMAP) amplitude ratio and injured-to-contralateral gastrocnemius wet weight ratio were 2.3- and 1.5-fold those of hollow conduits, reaching 88% and 92% of the corresponding autograft values, respectively. These outcomes were accompanied by improved axon- and Schwann cell-associated regeneration, myelin ultrastructure, and target muscle preservation. Proteomics associated P-RGI@RA treatment with cytoskeletal regulation, extracellular matrix remodeling, axon guidance, and inflammation-related pathways, while immunoblotting showed increased phosphorylation of phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK). This conduit-hydrogel system provides a potential strategy for peripheral nerve regeneration.

Rational design of polycationic gene delivery vectors requires understanding how polymer chemistry governs RNA complexation, cellular uptake, and intracellular release kinetics. Poly(dimethylaminoethyl methacrylate) brushes were found to display striking potential for the delivery of siRNA, with high knockdown efficiency and low cytotoxicity. However, the impact of the physico-chemistry of a broader range of polymer brushes on RNA delivery has not been explored. Using a library of 10 cationic polymer brushes spanning tertiary amine and quaternary ammonium chemistries, we reveal how hydrophobicity, pKa, rigidity, and quaternisation modulate siRNA delivery and gene silencing. Combining ellipsometry and surface plasmon resonance, we find that RNA binding capacity correlates directly with pH-responsiveness and the chain rigidity of brushes. Quaternisation with short methyl groups fundamentally altered binding mechanisms, eliminating pH sensitivity while improving colloidal stability and reducing cytotoxicity. To investigate the impact of the physico-chemical properties on transfection efficiency, the uptake of brush-RNA complexes was examined by confocal microscopy and flow cytometry and we quantified cytosolic release using a competitive binding microscopic assay. We observe excellent correlation between the impact of the brush physico-chemistry on release kinetics and long term silencing efficiency. Remarkably, we report that the binding capacity of RNA within brushes does not always correlate with cellular internalisation, competitive desorption and transfection efficiency: rigid imidazole brushes achieved robust gene silencing despite binding substantially less RNA than poly(alkylamine methacrylate) brushes. These findings expand the delivery vector design space, enabling the rational engineering of next-generation polymeric carriers for controlled RNA delivery kinetics.

Matrix-bound nanovesicles (MBVs) are a recently discovered subclass of small extracellular vesicles (EVs) that reside within the extracellular matrix of non-mineralized tissues throughout the body. Functionally, MBVs exhibit unique immunomodulatory properties that have been leveraged therapeutically to treat various tissue pathologies, including periprosthetic osteolysis, rheumatoid arthritis, and skeletal muscle injury. However, like other EVs, the therapeutic efficacy of MBV applications is limited by delivery methods, namely bolus injections, that offer poor control of EV persistence and bioavailability at the site of administration. We hypothesized that a superior MBV delivery platform could be developed by entrapping MBVs in a tunable, engineered alginate matrix to control retention and release of MBVs on therapeutically relevant timescales. To this end, we encapsulated dermal fibroblast MBVs in bioinert alginate hydrogels with varying stiffness and stress relaxation rates to determine the impact of matrix mechanical properties on MBV release and retention over a 14-day period. We found that stiffer matrices increased MBV release and decreased MBV retention compared to their softer counterparts. Additionally, fast-relaxing matrices retained fewer MBVs than slow-relaxing matrices regardless of differences in matrix stiffness. We then compared our results to synthetic liposomes and found these results mirror our MBV results, demonstrating that alginate materials may be utilized for more precise control of EV and liposome delivery in the body and may overcome limitations associated with current EV administration methods.

Corneal defects pose a significant threat to visual function, underscoring the need for advanced transplantable artificial corneas. Collagen-based biomimetic scaffolds offer a promising avenue for corneal regeneration. However, the impact of collagen's hierarchical architecture on scaffold properties and its role in corneal healing remains incompletely understood. In this study, we systematically compared two distinct high-density collagen membranes: a fibrous collagen membrane (FCM), fabricated via thermally controlled vitrification to induce collagen self-assembly, and a non-fibrous collagen membrane (NFCM), prepared by chemical crosslinking followed by vitrification drying. The FCM dried at 37 °C exhibited well-aligned collagen fibrils and lamellar organization, along with thermal stability, hydration capacity, and mechanical behavior closely resembling those properties of the native cornea. In contrast, the NFCM, while mechanically brittle, possessed a smooth surface that markedly promoted epithelial cell migration. Leveraging these distinct properties, we constructed a bilayer collagen composite comprising an upper NFCM layer and a lower FCM layer, designed to synergistically facilitate rapid epithelial wound closure and robust stromal integration, respectively. Our findings underscore the pivotal role of collagen microstructure in determining the mechanical, optical, and biological performance of corneal scaffolds, and provide a rational design strategy for developing hierarchically structured collagen membrane composites with translational potential for corneal repair.