Background and objective <p>Sepsis-related acute lung injury (S-ALI) had become an important public health issue worldwide. However, the mechanism of S-ALI was still not fully understood. This study aims to investigate the possibility of exosomes secreted from endothelial progenitor cells (EPCs) serving as a carrier for microRNA (miR)-218 to alleviate S-ALI and explore the possible mechanism.</p> Methods <p>Exosomes were isolated from EPCs of C57BL/6J mice using differential centrifugation. Exosomes tracking in vivo and their uptake by EPCs in vitro were detected. miR-218 inhibitor and mimic were applied to investigate its function in mice and regulating polarization of alveolar macrophages (AMs). Bioinformatics and dual-luciferase reporter gene assays were used to explore the downstream targets of miR-218. si-HMGA1 and oe-HMGA1 were used to investigate its function in regulating polarization of AMs. Rescue experiments were carried out to uncover the interaction between miR-218 and HMGA1 in AMs.</p> Results <p>Exosomes were isolated from EPCs and confirmed their accumulation in the mice lung as well as their uptake by AMs in vitro. In vivo, miR-218 transferred by exosomes secreted from EPCs mitigated ALI. In vitro, miR-218 inhibitor enhanced LPS-induced polarization of M1 macrophages, while miR-218 mimic suppressed these reactions. HMGA1 was confirmed as a target gene of miR-218, and its over-expression offset the protective effects of miR-218.</p> Conclusions <p>miR-218 transferred by exosomes secreted from EPCs mitigated ALI in septic mice by inhibiting HMHA1 which regulates macrophages polarization.</p>