NIR Light‐Controlled Cascade Regulation of Mixed‐Valence Copper (I)/(II) Nanozyme (Cu 2−x Se) Spray for Infectious Wound Healing

Abstract The widespread abuse of antibiotics has led to the emergence of drug‐resistant bacterial strains, severely complicating the treatment of infectious wounds. Traditional therapies are often limited to antibacterial or anti‐inflammatory approaches, making it challenging to manage both early‐stage infection and later‐stage tissue regeneration simultaneously. Herein, a Cu 2−x Se nanoparticles (CSNPs) spray containing mixed‐valence copper ions, enabling the programmed healing of infectious wounds is developed through light‐controlled cascade regulation. In the early infection stages, the copper ions released from CSNPs exert antibacterial effects via chemodynamic therapy (CDT), with their activity significantly enhanced under near‐infrared (NIR) irradiation. At later stages, Cu 2+ /Cu + ions enter cells, interact with cysteine residues in KEAP1 protein, and induce conformational changes, triggering deubiquitinase activity and suppressing macrophage‐driven inflammation. Findings from in vitro and in vivo studies consistently revealed that CSNPs efficiently depleted glutathione and enhanced H 2 O 2 breakdown, leading to the generation of •OH and O 2 •‐ under NIR exposure, which resulted in an MRSA elimination rate exceeding 99%. Mechanistically, CSNPs bind to KEAP1, removing the ubiquitin linkage from NRF2, thereby inhibiting inflammation. This CSNPs spray provides a dual synergistic effect of antimicrobial and tissue‐regenerative properties, offering an innovative approach for treating antibiotic‐resistant infections in wounds.