NIR Light-Controlled Cascade Regulation of Mixed-Valence Copper (I)/(II) Nanozyme (Cu2−xSe) Spray for Infectious Wound Healing

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.