H₂S-Driven Copper Redox Cycling Integrates Direct Bactericidal Activity and Macrophage Immunomodulation for Enhanced MRSA Clearance at Low-dose Copper

This study reports a hydrogen sulfide (H₂S)-driven copper redox cycling system that synergizes direct bactericidal activity and macrophage immunomodulation for methicillin-resistant Staphylococcus aureus (MRSA) clearance at subtoxic copper doses. By coupling oxygen-mediated oxidation with sulfide-driven reduction, the system achieves ‌self-sustaining Cu(II)/Cu(I) cycling‌, maintaining bioactive Cu(I) regeneration (30.8–50.6% reduction efficiency over 8 days) under physiological redox equilibrium. At an ultralow total copper dose (12.5 μM), the dual-action mechanism delivers ‌67.3% MRSA growth inhibition‌ via Cu(I)-mediated bactericidal effects and ‌86.1% intracellular MRSA suppression‌ through Cu(II)-activated macrophage polarization. Comparative studies demonstrate a ‌2.1-fold enhancement in antibacterial potency‌ over Cu(II) monotherapy, alongside robust M1 macrophage activation characterized by TNF-α/IL-6 upregulation (ELISA) and M2-to-M1 phenotype transition (RT-PCR). The system preserves host cell viability (>80%) and disrupts MRSA immune evasion through redox-triggered immunometabolic reprogramming. This work establishes a paradigm for metal-based antimicrobials, integrating pathogen-targeting and host-directed strategies to combat antibiotic-resistant infections with minimal metal burden.