High-entropy alloy Janus artificial enzymes for pH-gated sequential redox therapy of drug-resistant bacterial infection

Drug-resistant bacterial infections in chronic wounds remain a critical challenge, particularly under persistent inflammation. Here, we report the de novo design of high-entropy alloy (HEA, PtFeCuCoNi)-based Janus artificial enzymes with pH-gated redox biocatalysis for sequential antibacterial and repair functions. The multi-metal synergy stabilizes the d-band center, allowing acidic oxidase/peroxidase-like activity and neutral antioxidase-like activity. In infection, the enzymes generate bactericidal reactive oxygen species (ROS) to eliminate methicillin-resistant Staphylococcus aureus (MRSA) and biofilms at ultralow concentrations (8 μg/mL). During healing, they scavenge ROS, alleviate oxidative injury and support cellular proliferation. In MRSA-infected wounds, this dual-action system clears bacteria and then accelerates regeneration through enhanced neovascularization and matrix remodeling. Mechanistic analyses reveal PFKFB3-mediated metabolic reprogramming, suppression of pro-inflammatory cytokines, and macrophage polarization toward the M2 phenotype. Integrating pH-gated antimicrobial and immunomodulatory repair within one nanoplatform, this strategy addresses the conflicting demands of infection control and tissue healing.