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

ABSTRACT 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.