A Self‐Reinforcing Hydrogel Orchestrates Dynamic Microenvironment Reprogramming for High‐Quality Diabetic Skin Regeneration

Chronic diabetic wounds are characterized by persistent inflammation, bacterial infection, oxidative stress, hypoxia, impaired angiogenesis, and pathological fibrosis. Herein, a self‐reinforcing hydrogel dressing (RNPP) is developed by integrating copper peroxide (CuO 2 )/manganese dioxide (MnO 2 ) hybrid nanozymes and ginsenoside Rg1 (Rg1) into a sodium polyacrylate/polymetformin matrix for wound microenvironment regulation and high‐quality diabetic wound healing. RNPP rapidly promotes hemostasis, absorbs exudate, and maintains a moist protective interface. CuO 2 /MnO 2 nanozymes provide non‐antibiotic antibacterial activity through Cu 2+ release while scavenging excessive reactive oxygen species and converting endogenous H 2 O 2 into oxygen, thereby alleviating oxidative stress and hypoxia, promoting pro‐regenerative macrophage polarization, angiogenesis, and re‐epithelialization. Meanwhile, released Cu 2+ dynamically coordinates with polymetformin, reducing free Cu 2+ toxicity while reinforcing the hydrogel network. Sustained Rg1 release further modulates the transforming growth factor‐β1 (TGF‐β1)/α‐smooth muscle actin (α‐SMA) axis and suppresses myofibroblast overactivation, thereby attenuating fibrotic signaling and promoting organized collagen remodeling. These effects suggest a favorable microenvironment for improved tissue remodeling. Consequently, RNPP accelerates tissue repair in diabetic and MRSA‐infected wounds while favoring regenerative tissue remodeling, providing a multifunctional material strategy for chronic wound management.