A Self-Oxygenating Nanozyme Cascade System for Drug-Resistant Bacterial Infected Diabetic Wound Healing

Abstract

Chronic diabetic wounds remain challenging due to biofilm-associated antibiotic resistance, persistent hypoxia, and dysregulated inflammation. Here, we develop a copper-doped iron oxide nanozyme (CFO@PEG NPs) that synergizes with H₂O₂ to establish a trienzyme catalytic cascade for diabetic wound regeneration. The material exhibits peroxidase-, glutathione peroxidase-, and catalase-like activities, enabling continuous ROS generation, antioxidant depletion, and hypoxia alleviation. Physicochemical characterization confirms cubic CuFe₂O₄ nanostructures (200 nm) with coexisting Cu²⁺/Cu⁺ and Fe³⁺/Fe²⁺ redox pairs, which enhance charge transfer kinetics and multienzyme synergism. In vitro, CFO@PEG NPs (75 μg/mL) eradicate 99.9% of methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Escherichia coli (MREA) while clearing 90% of biofilms. In vivo, the system accelerates healing of MRSA-infected diabetic wounds through three interconnected mechanisms: (1) ROS-mediated bacterial membrane disruption, (2) catalase-driven O₂ generation that reduces HIF-1α expression and increases CD31 neovessels, and (3) immunomodulation shifting macrophages from pro-inflammatory M1 (TNF-α: 8.5 vs 90.1 pg/mL) to reparative M2 phenotypes (IL-10:103.7 vs 21.8 pg/mL). Full wound closure is achieved within 8 days without systemic toxicity. This work provides a paradigm for engineering nanozyme cascades to address the multidimensional challenges in chronic infected wound therapy.