In situ arming of NETs for targeted delivery of redox-modulating liposomes to eradicate intracellular bacteria in sepsis

Sepsis is a life-threatening syndrome caused by dysregulated host responses to bacterial infection. Persistence of intracellular bacteria within macrophages sustains excessive reactive oxygen species (ROS) production, disrupts redox homeostasis and amplifies inflammatory cascades that accelerate disease progression. Here, we developed an in situ arming strategy that generated potent antibacterial effectors by programming neutrophil extracellular traps with redox-modulating liposomes (SUPER-NETs) for targeted sepsis treatment. SUPER-NETs are formed in vivo through neutrophil hijacking and co-migration to infection sites, and subsequent functionalization of expelled NETs. Notably, SUPER-NETs established a neutrophil–macrophage bridging interaction that enabled precise and efficient elimination of intracellular bacteria. In parallel, SUPER-NETs alleviated macrophage oxidative stress and dampened cytokine storm by activating the Nrf2 signaling pathway. In a severe murine sepsis model, systemic administration of SUPER-NETs conferred superior antibacterial efficacy, attenuated multi-organ injury, and significantly improved survival. Therefore, this in situ arming strategy of SUPER-NETs offers a promising therapeutic paradigm for sepsis by precisely eliminating intracellular bacteria and orchestrating macrophage redox homeostasis, with potential implications for the treatment of sepsis and other severe infectious diseases.