The misuse of antibiotics has led to a dramatic increase in bacterial resistance, creating an urgent need for efficient antimicrobial agents with multiple mechanisms of action. In this study, Cu was modified with berberine derivatives, and a core−shell structure was successfully developed, resulting in a light/pHresponsive CuHDB@CaP nanotherapeutic platform. It achieves controlled release of CuHDB nanozymes, with CaP, which is highly stable in neutral or alkaline environments, preventing CuHDB leakage and effectively "switching off" the activity of nanozymes. Bacterial metabolism, which produces lactic and keto acids, lowers the pH of the wound microenvironment. Additionally, exposure to 1064 nm near-infrared (NIR) light causes the CaP shell structure to collapse, releasing CuHDB nanozymes and "switching on" their enzyme-like activity. This enables the CuHDB@CaP nanotherapeutic platform to be both safe and highly efficient. CuHDB exhibits not only a strong photothermal effect but also enhanced glutathione oxidase (GSHOx)-like and peroxidase (POD)-like enzyme activities. The GSHOx-like activity contributes to the generation of H 2 O 2 , and its excellent H 2 O 2 affinity allows it to efficiently catalyze the conversion of H 2 O 2 to a sufficient amount of •OH through POD-like activity. This self-cascading catalytic platform does not require the introduction of additional H 2 O 2 and also promotes the consumption of GSH in the wound infection microenvironment. CuHDB@CaP can kill up to 99.0% of MRSA and Amp r E. coli, effectively inhibit biofilm formation without the emergence of drug resistance, and exhibit negligible cytotoxicity and hemolysis. Treatment experiments in mouse wound infection models showed that CuHDB@CaP combined with NIR could effectively treat wound infections and accelerate wound healing with minimal toxicity to normal tissue cells, demonstrating its potential for the clinical treatment of skin infections.
