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

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This work reports a H₂S‑driven Cu(II)/Cu(I) redox‑cycling system for *in‑vitro* MRSA clearance at subtoxic copper levels, combining direct bactericidal and macrophage‑immunomodulatory actions. Sustained Cu(I) regeneration (30.8–50.6% over 8 d) at 12.5 μM copper inhibited 67.3% extracellular MRSA and cleared 86.1% intracellular MRSA in RAW264.7 macrophages, far exceeding Cu(II) monotherapy (14.3%). This was accompanied by Cu(I)‑associated M1 polarization (TNF‑α↑, IL‑10↓, M2→M1 switch), while maintaining >80% host viability. This metal‑based, host‑directed antimicrobial strategy supports copper‑dose reduction; in‑vivo efficacy remains to be established.

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