Engineered Nanozyme-Hydrogel Spray with Microwave-Fueled Self-Amplifying Catalysis for Precise Methicillin-Resistant Staphylococcus aureus -Infected Diabetic Wound Therapy

Abstract

Diabetic chronic wounds present formidable clinical challenges due to a vicious cycle of methicillin-resistant Staphylococcus aureus (MRSA) infections, persistent hypoxia, and chronic inflammation. We herein report a sprayable and rapidly photo-cross-linkable hydrogel (LMG@GH-MA) that integrates a specially engineered microwave (MW)-responsive luteolin-based nanozyme (Lut-Mn/MnO2) with glucose oxidase (GOx). The rational design features a notable Mn4+/Mn3+ mixed-valence state in the nanozyme, which not only exhibits superior multienzyme-like activities but also serves as a robust MW susceptor, converting electromagnetic energy into localized mild hyperthermia (40.4 °C). This thermal activation enables self-amplifying catalytic cascade, where heat-enhanced GOx consumes wound glucose to produce H2O2, which is then efficiently converted into therapeutic oxygen by the heat-augmented Lut-Mn/MnO2, thereby synchronously alleviating hyperglycemia and hypoxia. Furthermore, the system achieves potent antibiotic-free antibacterial efficacy (99.19% ± 0.14%) against MRSA through a combined assault of physical membrane disruption and profound metabolic interference. The MRSA-infected diabetic rat model confirms superior therapeutic outcomes, including near-complete wound closure by Day 12, effective MRSA clearance, and reduced inflammation. Crucially, we provide strong functional evidence that LMG@GH-MA actively remodels the immune microenvironment by suppressing key pro-inflammatory pathways (e.g., IL-17, TNF-α), thereby shifting the wound milieu from a chronic inflammatory state to a pro-regenerative one. Our work integrates an approach that merges advanced nanotechnology with accessible physical stimuli, offering a promising strategy that warrants further investigation for intractable diabetic wound regeneration.