Manganese‐Based Biofunctional 2D Nanosheets Enabled In Situ Macrophage Engineering for Precise Eradication of Osteomyelitis

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.