Manganese enhances macrophage bactericidal activity in mice with Staphylococcus aureus osteomyelitis via Sirt3-mitophagy axis

Staphylococcus aureus (S. aureus)-induced osteomyelitis remains challenging in clinical practice, wherein macrophages with impaired bactericidal function serve as reservoirs for intracellular bacterial survival, contributing to persistent and relapsing infections. Here, we show that exogenous manganese (Mn2+) enhances the bactericidal capacity of S. aureus-infected macrophages. By repressing the mitochondrial protein Sirt3, Mn2+ inhibits S. aureus-induced mitophagy via the PTEN-induced kinase 1/parkin pathway, thereby boosting the production of mitochondrial reactive oxygen species to eradicate intracellular bacteria. Pharmacological activation or genetic overexpression of Sirt3 abolishes these effects, identifying this axis as a key molecular target of Mn2+. Based on this, we further develop a biomimetic nanotherapeutic system for targeted Mn2+ delivery. In a mouse model of osteomyelitis, this nanosystem precisely represses Sirt3 in macrophages within the infected medullary cavity, markedly reduces bacterial burden, and effectively alleviates bone destruction. Our findings implicate an immunomodulatory mechanism by which Mn2+ enhances macrophage bactericidal activity and develops a potent Mn2+-based metalloimmunotherapeutical strategy for S. aureus-induced osteomyelitis. Staphylococcus aureus-induced osteomyelitis is therapeutically challenging, and macrophages can serve as reservoirs for intracellular bacterial persistence. Here the authors show that Mn2+ enhances macrophage bactericidal activity by repressing the Sirt3-mitophagy axis, and develop a biomimetic manganese-based nanosystem that alleviates osteomyelitis in mice.