Glucose-Activated Nanoreactor Initiating Cascade Reaction to Remodel Immune Microenvironment for Promoting Diabetic Wound Healing

Diabetic wound healing represents a formidable clinical challenge due to the complex pathological microenvironment characterized by hyperglycemia, persistent hypoxia, and excessive oxidative stress. Single-enzyme therapies struggle to address these issues in a coordinated and sequential manner. To overcome this limitation, an innovative integrated nanozyme system, MCP@G, was developed to intelligently remodel the diabetic wound microenvironment. This system seamlessly integrated glucose oxidase (GOx) with a Pt-deposited Mn-doped Ce metal-organic framework (MOF) nanozyme that exhibited mimic activities of superoxide dismutase (SOD) and catalase (CAT). MCP@G initiated a self-enhancing cascade catalytic reaction: GOx consumed local glucose and oxygen, alleviating hyperglycemia while generating H₂O₂. Subsequently, the SOD-mimic component scavenged superoxide anions (•O₂⁻), producing H₂O₂ and O₂. Finally, the CAT-mimic activity decomposed the accumulated H₂O₂ into water and oxygen, thereby mitigating oxidative stress while simultaneously supplying oxygen for the GOx reaction and cellular respiration. This cascade effectively broke the vicious cycle of hyperglycemia, hypoxia, and oxidative stress. Both in vitro and in vivo experiments demonstrated that MCP@G significantly alleviated mitochondrial oxidative stress, modulated the expression of anti-inflammatory factors, enhanced fibroblast migration, and promoted mature blood vessel formation. Consequently, in a diabetic rat model, MCP@G treatment accelerated wound closure, accompanied by robust collagen deposition and significant hair follicle regeneration. This multienzyme mimicking strategy provided a powerful and promising platform for treating refractory diabetic wounds.