Glucose-Responsive Antibacterial Nanogel for Synergistic Dual-Mode Therapy of Diabetic Wound Infections via Enhancing Cascade Generation of Hydroxyl Radicals and Hypoxia-Induced Activation of Metronidazole

Pathogen colonization causes tissue damage, chronic inflammation, and antimicrobial resistance, leading to nonhealing wounds. Moreover, bacteria-infected diabetic wounds are particularly difficult to heal owing to persistent hyperglycemia. Herein, a glucose (Glu)-responsive antibacterial nanogel (PAMGHM) consisting of polyacrylamide (PAM) loaded with glucose oxidase (GOx), horseradish peroxidase (HRP), and metronidazole (MTZ) is rationally constructed for combating the diabetic wound infections. This nanogel was fabricated via a reverse microemulsion polymerization approach, which enabled the co-encapsulation of GOx and HRP within nanoscale gel microspheres. Within PAMGHM, GOx first catalyzes the oxidation of Glu to produce H₂O₂, which is subsequently utilized by HRP to generate hydroxyl radicals (•OH). The close integration of cascade enzymes ensures rapid Glu consumption and •OH production, which not only directly kills bacteria but also establishes a localized hypoxic microenvironment through O₂ depletion. The induced hypoxia promotes bacterial nitroreductase expression, thereby activating the antibacterial properties of MTZ. <i>In vitro</i> experiments reveal that PAMGHM exhibited a powerful killing effect against both Staphylococcus aureus and Escherichia coli, demonstrating synergistic chemodynamic/chemo dual-mode antibacterial therapy. Further <i>in vivo</i> assays exhibit that the proposed PAMGHM accelerates diabetic wound healing by killing bacteria and alleviating hyperglycemia-induced inflammation. This cascade enzyme-mediated antibiotic activation strategy offers a useful therapeutic approach to meet the requirements of efficient antibacterial therapy, hyperglycemia control, and anti-inflammation, showing great potential in the treatment of chronic diabetic wound infections.