Efficient treatment of osteomyelitis caused by Staphylococcus aureus is a great clinical challenge due to bacterial resistance and immune evasion issues. Macrophages play a crucial role in the fight against S. aureus but suffer from deficiencies in function in the infectious milieu leading to persistent infection. Here, a strategy of exploiting aged neutrophil membrane (aNM) is developed to camouflage 2D MnPSe3 nanosheets (MPS NSs), denoted as aNM@MPS, to mediate in situ macrophage engineering, thereby potentiating macrophages to eradicate refractory osteomyelitis. When administered systematically, the biofunctional aNM@MPS ensures selectivity for osteomyelitis lesions, enhanced bone marrow retention, and subsequent phagocytosis by macrophages. In the mouse model of osteomyelitis, the aNM@MPS enables dysfunctional macrophages to digest intracellular bacteria by generating highly toxic hydroxyl radicals and sequentially reprogramming bactericidal immunity through manganese ion-mediated immune activation, which synergistically terminates persistent infection-initiated pathological cascades and subsequently reestablish host-directed bactericidal potency, thereby conferring a satisfactory osteoprotective effect. These findings demonstrate that macrophages in the skeletal infectious milieu can be precisely remodeled via the lesion-macrophage dual-targeting metalloimmunotherapy strategy, which holds potential for osteomyelitis treatment.

Department of Inorganic Chemistry University of Chemistry and Technology Prague Technicka 5 166 28 Prague 6 Czech Republic

Department of Neurology Beijing Tiantan Hospital Capital Medical University Beijing 100070 China

Department of Physics Department of Materials Science and Engineering and Department of Biomedical Engineering City University of Hong Kong Tat Chee Avenue Kowloon Hong Kong 999077 China

School of Interdisciplinary Science Beijing Institute of Technology Beijing 100081 China

School of Medical Technology Beijing Institute of Technology Beijing 100081 China

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