Lactiplantibacillus plantarum, Extracellular vesicles, Acute lung injury, Ferroptosis, Macrophages, Biotechnology, TP248.13-248.65, Medical technology, R855-855.5

Abstract Despite considerable advancements in understanding the mechanisms of ALI, the therapeutic options available in clinical practice remain predominantly supportive, highlighting the urgent need for innovative treatments. In this study, we investigated the potential protective benefits of extracellular vehicles from the probiotic strain Lactiplantibacillus plantarum (LpEVs) in ALI mouse model. We revealed that LpEVs administration attenuated LPS-induced ALI, as evidenced by reduced lung pathology, decreased inflammatory markers, and mitigated ferroptosis. In vitro experiments demonstrated that LpEVs restrained ferroptosis and promoted a shift towards an anti-inflammatory macrophage phenotype. Moreover, LpEVs increased the expression of NRF2, resulting in the promotion of HO1 and strengthening anti-ferroptotic System Xc-/GPX4 axis. Our analysis revealed that LpEVs alleviated ALI through the suppression of macrophages ferroptosis by delivering cbn-let-7 targeting ferroptosis-related gene Acsl4. These findings propose LpEVs as a promising therapeutic approach for preventing and treating ALI, highlighting the potential of leveraging probiotic-derived biomolecules to develop novel therapeutic strategies.