Electron-rearranged CuMg@ZIF nanoplatform for pH-Responsive sequential therapy: From infection eradication to neuroangiogenesis in diabetic wounds

Pathological microenvironment of diabetic wounds greatly increases bacterial infection, hyperinflammation, vasculopathy and neuropathy, impeding wound healing. To address these issues, a Cu and Mg codoped ZIF-8 (CuMg@ZIF) nanoplatform with pH-responsive degradation and multi-enzyme activities (peroxidase (POD)-like activity, superoxide dismutase (SOD)- and catalase (CAT)- activity) was constructed. Density functional theory (DFT) calculations reveal that Cu and Mg doping induce stretching of metal-N bonds and electron rearrangement in ZIF framework, which enhance degradation and subsequent ion releasing in acidic microenvironment, and increase Cu⁺/Cu²⁺ ratio to improve multi-enzyme activities. CuMg@ZIF exhibits excellent antibacterial efficiencies (100% against S. aureus and 99.98% against E. coli) at a low concentration (50 μg/ml) via rapid metal ion releasing and •OH generation. After sterilization, the SOD- and CAT-like activities, along with the moderate release of ions from the CuMg@ZIF scavenge ROS and facilitate macrophage recovery and M2 phenotype polarization to inhibit inflammatory reaction and secrete anti-inflammatory cytokines, which further enhance the biofunctions of endothelial cells, neural cells, and fibroblasts. This study provides a promising pH sensitive therapy to eliminate infection, promote immunoregulation, neuroangiogenesis and ECM remodeling, thereby accelerating the diabetic wound repair process.