Copper peptide activated cascade catalysis for glucose regulation and hypoxia reversing in infected diabetic wound healing

Starvation therapy has emerged as a promising strategy in diabetic wounds treating by regulating glucose level to deplete microbial nutrients without inducing antimicrobial resistance. However, this process consumes large amounts of oxygen, exacerbating wound hypoxia and compromising therapeutic efficacy. In this study, we designed a GOX-loaded hydrogel incorporated with copper peptide (GHK-Cu) to construct a copper peptide-activated cascade catalysis system for concurrent glucose regulation and hypoxia reversing. GOX initiates the cascade by catalyzing glucose oxidation, which reduces local hyperglycemia levels and generates hydrogen peroxide (H 2 O 2 ). Subsequently, copper ions in GHK-Cu activate the subsequent step by mediating the decomposition of H 2 O 2 through a catalase(CAT)-like reaction, releasing local oxygen to effectively alleviate the hypoxic state of the wound, and its own biological activity can further promote skin repair. The research results show that the Gel@GHK-Cu/GOX hydrogel can efficiently facilitates the decomposition of glucose into oxygen via the cascade reaction. Moreover, this hydrogel has been confirmed to have multiple therapeutic effects, including antibacterial activity, tissue repair promotion, antioxidant capacity, and angiogenesis stimulation. In conclusion, the Gel@GHK-Cu/GOX hydrogel provides an effective approach for chronic diabetic wound therapy. Its multifunctional synergistic mechanism offers novel insights for addressing clinical challenges in refractory diabetic wound healing.