Objective To investigate the effect and potential mechanism of bone marrow mesenchymal stem cells (BMSCs) – derived extracellular vesicles (EVs) on lung tissue injury in mice with severe acute pancreatitis (SAP). Methods 24 SPF grade male C57BL/6 mice and primary mouse lung microvascular endothelial cells(PMVEC) were selected. Divide the mice into sham group (sham group), SAP group, and BMSC group, with 8 mice in each group. Divide mouse primary PMVEC into model group (NaTC group), BMSC-EV group, and control group (control group). Extraction and characterization of healthy mouse BMSCs and their derived extracellular vesicles (BMSC-EVs). A mouse model of severe acute pancreatitis (SAP) was established, and BMSC-EVs were injected into SAP mice by tail vein or intervened in PMVECs in vitro, to observe the pathological damage of pancreatic and lung tissues, the changes of serum amylase, lipase, and inflammatory factors [tumor necrosis factor α (TNFα), interleukin-6 (IL-6)], and the inflammatory factors of lung tissues and PMVECs, and the endothelial cell barrier related proteins [E-cadherin, ZO-1, intercellular cell adhesion molecule-1(ICAM-1)] expression, and tight junctions between PMVECs to explore the effects of BMSC-EVs on pancreatic and lung tissues in SAP mice and PMVECs in vitro. Results BMSCs have the potential for osteogenic, chondrogenic, and lipogenic differentiation, and the EVs derived from them have a typical cup-shaped structure with a diameter of 60-100 nm. BMSC-EVs expressed the extracellular vesicle-positive proteins TSG101 and CD63 and did not express the negative protein Calnexin. Compared with sham mice, SAP mice underwent significant pathological damage to the pancreas (P<0.05), and their serum amylase, lipase, inflammatory factor IL-6, and TNFα levels were significantly up-regulated (P<0.05); whereas, BMSC-EVs markedly ameliorated the pancreatic tissue damage in SAP mice (P<0.01), down-regulated the levels of peripheral serum amylase, lipase, IL-6 and TNFα (P<0.05), and up-regulated the level of anti-inflammatory factor IL-10 (P<0.05). In addition to this, SAP mice showed significant lung histopathological damage (P<0.05), higher neutrophils and macrophages infiltration (P<0.05), higher levels of the inflammatory factors TGFβ and IL-6 (P<0.05), as well as reduced barrier protein E-cadherin, ZO-1 expression and elevated expression of the intercellular adhesion protein ICAM-1 (P<0.05), BMSC-EVs significantly ameliorated lung histopathological injury, inflammatory cells infiltration, inflammatory factor levels, and expression of barrier proteins, and suppressed ICAM-1 expression (P < 0.05). In the in vitro PMVECs experiments, it was found that intercellular tight junctions were broken in the NaTC group, and the levels of inflammatory factors TNFα and IL-6 (P<0.05) were significantly up-regulated, the protein expression of E-cadherin and ZO-1 (P<0.05) was significantly down-regulated, and the expression of ICAM-1 (P<0.05) was significantly up-regulated. BMSC-EVs significantly improved intercellular tight junctions in the NaTC group and inhibited the secretion of TNFα and IL-6 (P<0.05), up-regulated the expression of the barrier proteins E-cadherin and ZO-1, and down-regulated the expression of ICAM-1 (P<0.05). Conclusion Bone marrow mesenchymal stem cell-derived extracellular vesicles ameliorate lung tissue injury in SAP mice by restoring the lung endothelial cell barrier and inhibiting inflammatory cell infiltration.