LFA‐1‐Engineered Extracellular Vesicles Deliver CD59 to Protect Endothelial Integrity in Acute Lung Injury

Acute lung injury (ALI) is a life‐threatening disorder characterized by pulmonary endothelial injury, vascular leakage, and hypoxemia, yet no targeted therapies are available to protect the lung vasculature. Dysregulated complement activation contributes to endothelial dysfunction through excessive deposition of the membrane attack complex (MAC), which disrupts endothelial barrier integrity. CD59 is a membrane‐bound complement inhibitor that protects endothelial cells (ECs) from MAC‐mediated injury, but its role and therapeutic potential in ALI remain unclear. In this study, we found that endothelial CD59 was significantly reduced during bacteria‐induced ALI and that Cd59 deficiency exacerbated pulmonary vascular leakage in mice. To supplement endothelial CD59, we engineered extracellular vesicles (EVs) expressing lymphocyte function‐associated antigen‐1 (LFA‐1) (EV LFA−1 ) to enhance delivery to activated endothelium. CD59‐loaded EVs (EV LFA−1 ‐CD59) preferentially targeted ECs, reduced endothelial MAC deposition and apoptosis, and preserved endothelial barrier integrity in experimental ALI. EV LFA−1 ‐CD59 also improved survival following bacterial infection. Collectively, these data establish diminished endothelial CD59 levels as a critical driver of complement‐driven vascular injury and highlight EV LFA−1 ‐mediated CD59 delivery as a promising therapeutic strategy for ALI.