Nanoparticle-Cross-Linked Smart Responsive Hydrogels for Antimicrobial, Anti-Inflammatory, and Antioxidant Treatment of Diabetic Wounds

Infected diabetic wounds are complicated by bacterial infection, oxidative stress, and hyperglycemia, limiting conventional monotherapies. Combination therapies suffer from uncontrolled release and poor responsiveness to pathological cues. Here, we report a nanoparticle-cross-linked hydrogel that integrates structural integrity with environment-triggered delivery. We utilized self-assembled epigallocatechin gallate (EGCG)-tobramycin (TOB) nanoparticles as dynamic cross-linkers within a phenylboronic acid-modified gelatin network. The engineered system provides dual-stage responsiveness: the hydrogel disassembles under the hallmark hyperglycemic and acidic conditions of diabetic wounds, releasing the nanoparticles, which then dissociate under acidity to synchronize drug release. Such sequential disassembly acts as a synergistic “one-two punch,” allowing EGCG to scavenge ROS and remodel the inflammatory microenvironment, while TOB provides prolonged antibacterial action. In vivo , the system significantly reduced bacterial load, accelerated epithelial regeneration, and promoted high-quality wound healing. By seamlessly coupling nanocontrolled release with microenvironmental sensing, we present a precision-engineered platform for the synergistic treatment of recalcitrant diabetic wounds.