Dual-engineering metalloimmunotherapy mediates Staphylococcus aureus virulence silencing and biofilm immune microenvironment reprogramming against implant-associated infections

Implant-associated infections (IAIs) caused by <i>Staphylococcus aureus</i> (<i>S. aureus</i>) are notoriously recalcitrant to treatment due to the self-reinforcing interplay between bacterial virulence and a suppressive biofilm immune microenvironment (BIME). Here, we present a dual-engineering metalloimmunotherapy nanoplatform that synchronously silences bacterial virulence and reprograms host immunity to eradicate IAIs. The nanoplatform, termed HMPF, integrates a fenoprofen-loaded, polydopamine-modified hollow MnO₂ core that is further cloaked with a macrophage-erythrocyte hybrid membrane, enabling bacteria-targeted delivery and hemolysin-responsive drug release. By inhibiting the SaeRS two-component system of <i>S. aureus</i>, HMPF suppresses virulence factor expression and disrupts biofilm structure, dismantling the physical barrier for immune cell infiltration. Simultaneously, Mn²⁺ release and mild photothermal stimulation activate the cGAS-STING and pattern recognition receptor pathways, reprogramming host BIME to enhance both innate and adaptive immune responses. Crucially, HMPF establishes pathogen-specific immune memory, which prevents infection recurrence, outperforming vancomycin in murine IAIs models. This pathogen-host dual-engineering strategy remains effective against other clinical <i>S. aureus</i> strains without inducing drug resistance, bridging virulence disarmament and immunomodulation to offer a transformative antibiotic alternative for resistant IAIs.