NIR-II/pH Dual Responsive\nCuHDB@CaP Nanospheres as\na Self-Cascading Catalytic Platform for Highly Efficient Combating\nBacterial Infections

The misuse of antibiotics has led to a dramatic increase\nin bacterial\nresistance, creating an urgent need for efficient antimicrobial agents\nwith multiple mechanisms of action. In this study, Cu was modified\nwith berberine derivatives, and a core–shell structure was\nsuccessfully developed, resulting in a light/pH-responsive CuHDB@CaP\nnanotherapeutic platform. It achieves controlled release of CuHDB\nnanozymes, with CaP, which is highly stable in neutral or alkaline\nenvironments, preventing CuHDB leakage and effectively “switching\noff” the activity of nanozymes. Bacterial metabolism, which\nproduces lactic and keto acids, lowers the pH of the wound microenvironment.\nAdditionally, exposure to 1064 nm near-infrared (NIR) light causes\nthe CaP shell structure to collapse, releasing CuHDB nanozymes and\n“switching on” their enzyme-like activity. This enables\nthe CuHDB@CaP nanotherapeutic platform to be both safe and highly\nefficient. CuHDB exhibits not only a strong photothermal effect but\nalso enhanced glutathione oxidase (GSHOx)-like and peroxidase (POD)-like\nenzyme activities. The GSHOx-like activity contributes to the generation\nof H<sub>2</sub>O<sub>2</sub>, and its excellent H<sub>2</sub>O<sub>2</sub> affinity allows it to efficiently catalyze the conversion\nof H<sub>2</sub>O<sub>2</sub> to a sufficient amount of •OH\nthrough POD-like activity. This self-cascading catalytic platform\ndoes not require the introduction of additional H<sub>2</sub>O<sub>2</sub> and also promotes the consumption of GSH in the wound infection\nmicroenvironment. CuHDB@CaP can kill up to 99.0% of MRSA and Amp<sup>r</sup>E. coli, effectively inhibit\nbiofilm formation without the emergence of drug resistance, and exhibit\nnegligible cytotoxicity and hemolysis. Treatment experiments in mouse\nwound infection models showed that CuHDB@CaP combined with NIR could\neffectively treat wound infections and accelerate wound healing with\nminimal toxicity to normal tissue cells, demonstrating its potential\nfor the clinical treatment of skin infections.