Lactobacillus reuteri extracellular vesicles alleviate septic liver injury via cGAS-STING-dependent macrophage reprogramming

Sepsis-associated liver injury (SALI) is highly lethal and primarily driven by dysregulated macrophage responses, yet safe and targeted interventions remain limited. Probiotic-derived bacterial extracellular vesicles (BEVs) offer a promising naturally-derived, cell-free nanotherapeutic alternative, but their precise immunomodulatory mechanisms and intracellular targets remain undefined. Here, we demonstrate that Lactobacillus reuteri-derived BEVs (BEV L. reuteri ) effectively mitigate SALI by reprogramming hepatic macrophages from a pro-inflammatory M1 toward a reparative M2 state. Mechanistically, internalized BEV L. reuteri preserve mitochondrial structural integrity and prevent the cytosolic leakage of mitochondrial DNA (mtDNA). This upstream protection significantly restricts the activation of the mtDNA-cGAS-STING-NF-κB inflammatory cascade, serving as a crucial blockade that drives the macrophages’ anti-inflammatory phenotypic switch. Furthermore, utilizing systemically administered myeloid-specific STING conditional knockout mice, we confirm that the hepatoprotective and systemic therapeutic effects of BEV L. reuteri strictly depend on the suppression of macrophage STING signaling. BEV L. reuteri fundamentally intercept the pathogenic mitochondria-STING crosstalk to resolve macrophage-driven systemic inflammation. These findings highlight the potential of utilizing specific Gram-positive bacterial nanovesicles as a biologically safe, highly biocompatible, and targeted nanotherapeutic strategy for sepsis and related severe acute inflammatory disorders. BEV L. reuteri protects against sepsis-induced liver injury by targeting the cGAS-STING signaling pathway. Internalized BEV L. reuteri prevent mitochondrial DNA leakage, thereby silencing the STING/NF-κB inflammatory cascade and restoring hepatic homeostasis