Platelet Membrane-fused Circulating Extracellular Vesicles Protect the Heart from Ischemia/reperfusion Injury.

Myocardial ischemia/reperfusion injury (I/RI) may potentiate cardiac remodeling and heart failure, while effective therapies for I/RI remain lacking. Circulating extracellular vesicles (EV) have great potential to protect against I/RI. However, effective delivery of EV in vivo remains a limiting factor for clinical application. The present study constructs a biomimetic delivery system of platelet membrane-fused circulating human plasma-derived EV (P-hEV), utilizing the natural affinity of platelets for EV delivery to the injured vascular and myocardial sites. The results show that platelet membrane and hEV membrane fusion can be achieved through repeated extrusion, producing P-hEV of small particle size. Compared to non-modified hEV, P-hEV uptake are greatly enhanced in human umbilical vein endothelial cells (HUVECs) stressed by oxygen glucose deprivation/reperfusion (OGD/R). Functionally, P-hEV inhibit HUVEC and neonatal rat cardiomyocyte (NRCM) apoptosis and promote HUVEC migration and tube formation under OGD/R stress in vitro. Intravenous delivery of P-hEV more effectively targets and accumulates at injury sites in the heart. Furthermore, P-hEV significantly enhance protection against acute I/RI and attenuate cardiac remodeling at three weeks post-I/RI. In conclusion, the platelet membrane-fused hEV delivery system enhances target delivery of EV to protect against myocardial I/RI, presenting a novel drug delivery system for ischemic heart diseases. This article is protected by copyright. All rights reserved.