Phosphatidylserine-everted erythrocyte membrane vesicles enhance efferocytosis and remodeling of vascular grafts

Erythrocytes and erythrocyte membrane vesicles have shown promise for personalized drug delivery through passive immune evasion, yet their active role in immune phagocytosis remains largely unexplored. Here, we introduce a paradigm based on phosphatidylserine-everted erythrocyte membrane vesicles that trigger efferocytosis, enabling immune-mediated tissue regeneration rather than immune evasion. Incorporation of these phosphatidylserine-everted erythrocyte membrane vesicles into small-diameter vascular grafts markedly enhances endothelialization, suppresses calcification, and improves long-term patency in a rabbit carotid artery replacement model. Preclinical evaluation in a large canine model further demonstrates superior performance compared with clinically used expanded polytetrafluoroethylene grafts. This study establishes engineered phosphatidylserine-everted erythrocyte membrane vesicles as a versatile, customizable, and cost-effective biointerface for vascular grafts and other blood-contacting devices, providing a compelling strategy to harness innate immune mechanisms for regenerative medicine. Erythrocyte membrane vesicles (EMVs) are promising for drug delivery but their role in immune-mediated regeneration is unclear. Here the authors show that phosphatidylserine-everted EMVs trigger efferocytosis to enhance endothelialization, reduce calcification, and improve vascular graft patency in animal models.