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Acute lung injury (ALI) is a severe respiratory disease with a high mortality rate. The integrity of the pulmonary endothelial barrier influences the development and prognosis of ALI. Therefore, it has become an important target for ALI treatment. Extracellular vesicles (EVs) are promising nanotherapeutic agents against ALI. Herein, endothelium-derived engineered extracellular vesicles (eEVs) that deliver microRNA-125b-5p (miRNA-125b) to lung tissues exerting a protective effect on endothelial barrier integrity are reported. eEVs that are modified with lung microvascular endothelial cell-targeting peptides (LET) exhibit a prolonged retention time in lung tissues and targeted lung microvascular endothelial cells in vivo and in vitro. To improve the efficacy of the EVs, miRNA-125b is loaded into EVs. Finally, LET-EVs-miRNA-125b is constructed. The results show that compared to the EVs, miRNA-125b, and EVs-miRNA-125b, LET-EVs-miRNA-125b exhibit the most significant treatment efficacy in ALI. Moreover, LET-EVs-miRNA-125b is found to have an important protective effect on endothelial barrier integrity by inhibiting cell apoptosis, promoting angiogenesis, and protecting intercellular junctions. Sequencing analysis reveals that LET-EVs-miRNA-125b downregulates early growth response-1 (EGR1) levels, which may be a potential mechanism of action. Taken together, these findings suggest that LET-EVs-miRNA-125b can treat ALI by protecting the endothelial barrier integrity., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)