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Abstract It is of great significance to develop a novel approach to treat bacterial infections, as the frequent misuse of antibiotics leads to the serious problem of bacterial resistance. This study proposed antibiotic-free antibacterial nanoparticles for eliminating methicillin-resistant Staphylococcus aureus (MRSA) based on a multi-model synergistic antibacterial ability of chemodynamic therapy (CDT), photothermal effect, and innate immunomodulation. Specifically, a polydopamine (PDA) layer coated and Ag nanoparticles loaded core-shell structure Fe3O4 nanoparticles (Fe3O4@PDA-Ag) is prepared. The Fe3O4 catalyzes H2O2 present in acidic microenvironment of bacterial infection into more toxic reactive oxygen species (ROS) and synergizes with the released Ag ions to exert a stronger bactericidal capacity, which can be augmented by photothermal action of PDA triggered by near-infrared light and loosen the biofilm by photothermal action to promote the penetration of ROS and Ag ion into the biofilm, result in disrupting biofilm structure along with killing encapsulated bacteria. Furthermore, Fe3O4@PDA-Ag exerts indirect antibacterial effects by promoting M1 macrophage polarizing. Animal models demonstrated that Fe3O4@PDA-Ag effectively controlled MRSA-induced infections through photothermal enhanced CDT, Ag+ releasing, and macrophage-mediated bactericidal properties. The acid-triggered antibacterial nanoparticles are expected to combat drug-resistant bacteria infection. Graphical abstract