Composite MOF hydrogel reprograms bacterial pigment metabolism for eliminating antibiotic-tolerant bacteria

The misuse of antibiotics has accelerated bacterial resistance, with methicillin-resistant Staphylococcus aureus (MRSA) posing a major global threat. Regulating bacterial metabolic pathways is a promising strategy, particularly pigment biosynthesis. Here, we engineered a hybrid hydrogel (Van@PCMOF@T/H) by embedding thymol and covalently anchoring a copper-phthalocyanine metal-organic framework (MOF) loaded with vancomycin (Van@PCMOF) within a methacrylated hyaluronic acid matrix. In a vancomycin-tolerant MRSA model (MRSA tol ), thymol effectively suppresses staphyloxanthin (STX) biosynthesis, thereby restoring bacterial susceptibility to vancomycin and oxidative stress. Upon near-infrared (NIR) activation, the system produces heat and reactive oxygen species and releases vancomycin together with copper ions, synergistically triggering cuproptosis, DNA damage, membrane destabilization, and biofilm disruption. In a murine skin-infection model, NIR-triggered treatment accelerates bacterial clearance, reduces inflammatory responses, and promotes wound healing. This metabolism-reprogramming platform provides an effective strategy to restore antimicrobial efficacy against antibiotic-tolerant bacterial infections.