GSH-depleted Cu-covalent organic frameworks for multimodal synergistic therapy against diabetic infections

Skin wound healing, particularly diabetic wound healing, is a common clinical challenge. Reducing bacterial infection and promoting angiogenesis are key strategies for diabetic wound healing. In this study, we construct the porphyrin-based Cu-covalent organic frameworks (Cu-COF) through a Schiff base condensation reaction, and then functionalize Cu-COF with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)] (mPEG-DSPE), denoted as PEG/Cu-COF, for enhancing diabetic wound healing. PEG/Cu-COF exhibits dual enzymatic properties (glutathione (GSH) oxidase-like and peroxidase (POD)-like nanozymes), facilitating the depletion of GSH and the generation of reactive oxygen species (ROS) through a self-cascading enzymatic reaction, thereby leading to chemodynamic therapy (CDT). Density functional theory (DFT) calculations are employed to investigate the catalytic mechanism and the results reveal that Cu-COF exhibits higher catalytic activity for POD. Moreover, porphyrin-based COF generates singlet oxygen and localize heating under white light and near-infrared irradiation, respectively. Both in vitro and in vivo experiments demonstrate that PEG/Cu-COF exhibits multimodal synergistic sterilization and promotes angiogenesis, collagen deposition, and re-epithelialization during diabetic wound healing. This work highlights the potential utilization of PEG/Cu-COF for self-supplying hydrogen peroxide (H2O2) and amplifying self-cascade reactions to address the limitations of enzymatic treatment, while the synergistic effect of phototherapy improves sterilization and minimizes side effects in vivo.