A biomimetic cascade nanoplatform for synergistic biofilm eradication and immune activation against MRSA

Methicillin-resistant Staphylococcus aureus (MRSA) biofilm-associated infections remain a formidable clinical challenge, owing to limited antibiotic penetration, an immunosuppressive microenvironment, and recurrent biofilm regeneration. Effective long-term immunomodulatory strategies to prevent reinfection are still lacking. To address this issue, we have constructed a biomimetic cascade nanoplatform (MACP@DG@CM) that integrates a photothermal nanozyme core, surface-anchored DNase I-functionalized gold nanoclusters (DNase I-GNCs), and a pre-activated macrophage membrane camouflage. This design enables synergistic biofilm eradication and immune microenvironment modulation. Under an 808 nm near-infrared (NIR) irradiation, the nanoplatform triggers a cascade radical storm, including photothermal hyperthermia, a peroxidase-like hydroxyl radical (·OH) burst, nitric oxide (NO) release, and DNase I-mediated extracellular DNA (eDNA) degradation. Concurrently, it depletes glutathione (GSH), disrupts bacterial redox homeostasis, and causes severe membrane damage. Transcriptomic analysis reveals that the nanoplatform perturbs bacterial two-component systems, d-amino acid metabolism, and antimicrobial peptide resistance pathways. Enzyme-linked immunosorbent assay (ELISA) further confirms up-regulated pro-inflammatory cytokines and down-regulated anti-inflammatory cytokines, indicating an activated inflammatory response. In an MRSA-infected wound model, it accelerates wound closure, promotes collagen deposition, and modulates inflammation. Collectively, this biomimetic cascade nanoplatform provides a synergistic strategy for biofilm eradication and immune activation against drug-resistant infections.