Accelerating chronic wound healing by breaking the pH limitations of biomolecule-loaded Nanozymes and remodeling the microenvironment in Cascade reactions

The microenvironment around the wounds of chronic disease patients often exhibits weakly alkaline conditions, primarily due to defects in the patients' blood glucose regulation, tissue hypoxia, accumulation of metabolic products, and bacterial infection and growth. To regulate the wound microenvironment across a broad pH range, a Fe-doped ZIF-8 nanozyme loaded with glucose oxidase (Fe-ZIF-8@GOx) was synthesized via a one-step in situ growth method. This nanozyme, with ZIF-8 serving both as a protective matrix and immobilization scaffold, enhances the enzyme's operational microenvironment and maintains functionality across a wide pH range. It exhibits the activities of cascade glucose oxidase (GOx), catalase-like (CAT-like), and peroxidase-like (POD-like) enzymes. When Fe-ZIF-8@GOx nanozymes encounter high glucose levels at the site of weakly alkaline chronic ulcers, the GOx particles catalyze the reduction of local pH, simultaneously triggering CAT-like enzyme activity to release O₂ and improve the wound microenvironment. The subsequent pH reduction induces the controlled release of iron ions, enabling Fe²⁺ to react with endogenously produced hydrogen peroxide to generate reactive oxygen species (ROS), conferring a distinctive guest–carrier synergistic antibacterial effect. Both in vitro and in vivo studies confirm that this material effectively reduces inflammation, modulates macrophage polarization, enhances collagen deposition, and promotes angiogenesis, ultimately accelerating wound healing under chronic diabetic conditions. Thus, our work not only overcomes microenvironmental limitations in antibacterial therapy but also offers a promising strategy for treating chronic diabetic infections.