Zinc peroxide-copper bimetallic nanozyme with self-activated ROS and cuproptosis for superficial antifungal therapy

Fungal infections, particularly intractable cases such as fungal keratitis (FK) and skin wound infections, remain a pressing global health challenge, further exacerbated by rising antifungal resistance and treatment-associated cytotoxicity. Herein, we report a highly effective, non-antibiotic therapeutic strategy integrating reactive oxygen species (ROS) generation and cuproptosis via ZnO₂ cores wrapped with a TA-Cu metal-phenolic network shell (ZnCu@TA) to combat fungi. Upon anchoring to fungal cell walls, ZnCu@TA responds to acidic microenvironments by releasing H₂O₂ and Zn²⁺ from the ZnO₂ core, thereby creates a concentrated burst of ROS that directly damages the cell wall, while promoting copper uptake to induce cuproptosis through mitochondrial dysfunction, leading to effective eradication of Candida albicans and biofilm disruption. In models of FK and skin wound infection, ZnCu@TA significantly reduced pathogens and inflammation with no observed adverse effects, and demonstrated promising preservation of visual function. These findings highlight ZnCu@TA as a safe and effective antifungal nanoplatform for treating superficial fungal infections, offering potential for clinical translation.