Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong, 226011, China.
Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai, 200444, China.
Adv Healthc Mater. 2023 Aug;12(21):e2300052. doi: 10.1002/adhm.202300052. Epub 2023 May 10.
Myocardial ischemia/reperfusion injury (I/RI) may potentiate cardiac remodeling and heart failure, while effective therapies for I/RI remain lacking. Circulating human plasma-derived extracellular vesicles (hEV) have great potential to protect against I/RI. However, the effective delivery of hEV in vivo remains a limiting factor for clinical application. The present study constructs a biomimetic delivery system of platelet membrane-fused hEV (P-hEV), utilizing the natural affinity of platelets for hEV delivery to the injured vascular and myocardial sites. The results show that platelet membrane and hEV membrane fusion can be achieved through repeated extrusion. Compared to non-modified hEV, P-hEV uptake is greatly enhanced in human umbilical vein endothelial cells (HUVECs) stressed by oxygen-glucose deprivation/reperfusion (OGD/R). Functionally, P-hEV inhibits HUVEC and neonatal rat cardiomyocyte (NRCM) apoptosis and promotes HUVECs 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 enhances protection against acute I/RI and attenuates cardiac remodeling at three weeks post-I/RI. In conclusion, the platelet membrane-fused hEV delivery system enhances the target delivery of EV to protect against myocardial I/RI, presenting a novel drug delivery system for ischemic heart diseases.
心肌缺血/再灌注损伤（I/RI）可能会增强心脏重构和心力衰竭，而有效的 I/RI 治疗方法仍然缺乏。循环的人血浆衍生细胞外囊泡（hEV）在预防 I/RI 方面具有巨大的潜力。然而，hEV 在体内的有效传递仍然是临床应用的一个限制因素。本研究构建了血小板膜融合 hEV（P-hEV）的仿生递药系统，利用血小板对 hEV 向损伤血管和心肌部位传递的天然亲和力。结果表明，通过反复挤压可以实现血小板膜和 hEV 膜的融合。与未修饰的 hEV 相比，在缺氧-葡萄糖再灌注（OGD/R）应激下，P-hEV 被人脐静脉内皮细胞（HUVEC）摄取的能力大大增强。在功能上，P-hEV 抑制 HUVEC 和新生大鼠心肌细胞（NRCM）凋亡，并促进 HUVEC 在 OGD/R 应激下的迁移和管形成。静脉内递送 P-hEV 更有效地靶向和积聚在心脏损伤部位。此外，P-hEV 显著增强了对急性 I/RI 的保护作用，并在 I/RI 后 3 周减轻了心脏重构。总之，血小板膜融合 hEV 递药系统增强了 EV 对心肌 I/RI 的靶向递送，为缺血性心脏病提供了一种新的药物递送系统。
