Cefazolin-loaded biomimetic mesoporous MnO2 nanoparticles for synergistic antibacterial and immune-modulating treatment of Staphylococcus aureus pneumonia.

First-generation cephalosporin cefazolin (CEF) is the clinical first-line antibiotic for treating Staphylococcus aureus pneumonia (SAP). However, its therapeutic efficacy remains limited due to high rates of resistance, a short plasma half-life, and insufficient accumulation at infection sites, which collectively result in suboptimal antibacterial activity and poor control of inflammation. To address these challenges, we developed a biomimetic mesoporous manganese dioxide nanocarrier (MnO2-CEF/MR) cloaked with hybrid macrophage-erythrocyte membranes (MR) to enable efficient pulmonary targeting of CEF while simultaneously releasing Mn2+ to activate the cGAS-STING signaling pathway and enhance innate immune responses. Our results demonstrate that MnO2-CEF/MR exhibits excellent stability and drug-release behavior, displays low cytotoxicity, and shows potent antibacterial activity against Staphylococcus aureus (S. aureus) in vitro, along with enhanced macrophage uptake and pronounced activation of cGAS-STING signaling. In a murine SAP model, MnO2-CEF/MR markedly activated the cGAS-STING pathway, which was accompanied by reduced pulmonary bacterial burden and alleviated tissue injury and inflammatory responses. In addition, the nanoplatform exhibited excellent hemocompatibility and biosafety, with no obvious hemolysis or organ toxicity. Collectively, these findings indicate that MnO2-CEF/MR achieves synergistic antibacterial and immunomodulatory effects against SAP through efficient CEF delivery and Mn2+-mediated activation of the cGAS-STING pathway, providing a promising strategy with potential clinical translational value for the treatment of SAP.