Pathology-adaptive sprayable hydrogel enables metal–metabolism–immune coordination for diabetic wound regeneration

Introduction Diabetic wounds are characterized by infection, oxidative stress, persistent inflammation, and impaired angiogenesis. This study developed a pathology-adaptive sprayable hydrogel for diabetic wound repair. Materials and methods A GelMA/HAMA hydrogel incorporating copper-based metal–organic framework nanoparticles and metformin was constructed through thiol–ene crosslinking and dynamic covalent interactions. Its physicochemical properties, responsive release, biological functions, and therapeutic efficacy were evaluated in vitro and in diabetic mouse skin and oral mucosal wound models. Results and discussion The hydrogel exhibited rapid gelation, sprayability, self-healing, wet-tissue adhesion, and microenvironment-responsive Cu²⁺/metformin release. It demonstrated antibacterial and cytocompatible properties while promoting cell migration and angiogenesis. Cu²⁺ was associated with HIF-1α/VEGF-related angiogenic signaling, whereas metformin activated AMPK, inhibited NF-κB signaling, and promoted reparative macrophage polarization. In vivo, the hydrogel accelerated wound closure, collagen deposition, re-epithelialization, and vascularization while reducing inflammation. Conclusion The hydrogel integrates responsive therapeutic release with antibacterial, angiogenic, and immunomodulatory effects, providing a promising approach for diabetic skin and oral mucosal wound repair.