ECM-Mimetic Silk Fibroin/GelMA Hydrogel Integrating Manganese Dioxide Nanozymes and Sustained Nitric Oxide Release for Sequential Immunomodulation and Healing of Chronic Infected Wounds.

BACKGROUND: Chronic infected diabetic wounds are difficult to heal because persistent bacterial colonization, oxidative stress, hypoxia, and prolonged inflammation disrupt the normal repair process. This study developed a multifunctional extracellular matrix (ECM)-mimetic hydrogel capable of simultaneously controlling infection, regulating the wound microenvironment, and promoting tissue regeneration. METHODS: A photocrosslinked silk fibroin/gelatin methacryloyl (SF/GelMA) hydrogel was engineered by incorporating hollow δ-MnO2 nanozymes and the nitric oxide donor S-nitrosoglutathione (GSNO) to construct the NO-GSNO@MnO2/SF-GelMA platform. Physicochemical properties, mechanical performance, nitric oxide release, oxygen generation, and antibacterial activity were characterized. Biological performance was evaluated through cytocompatibility, intracellular ROS scavenging, macrophage polarization, endothelial tube formation, and angiogenesis assays. Therapeutic efficacy was assessed in an MRSA-infected diabetic full-thickness wound model. RESULTS: The hydrogel formed a stable, porous network with improved mechanical properties and biocompatibility. Under acidic conditions, it achieved controlled nitric oxide release while MnO2 nanozymes catalytically converted hydrogen peroxide into oxygen, reducing oxidative stress and relieving hypoxia. The platform exhibited potent antibacterial activity against Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA), promoted macrophage polarization toward the regenerative M2 phenotype, enhanced endothelial tube formation, and stimulated neovascularization. In vivo, the hydrogel accelerated wound healing, achieving 96.8 ± 1.4% wound closure after 14 days, together with improved collagen remodeling, reduced inflammation, and enhanced vascular maturation. CONCLUSION: The NO-GSNO@MnO2/SF-GelMA hydrogel integrates antimicrobial activity, oxygen generation, ROS scavenging, and immunomodulation into a single biomaterial platform, providing an effective therapeutic strategy for chronic infected diabetic wound repair.