Engineered Mesenchymal Stem Cell–Derived Extracellular Vesicles Reverse Endothelial–Mesenchymal Transition in Atherosclerosis

Endothelial–mesenchymal transition (EndMT) of vascular endothelial cells (VECs) plays a pivotal role in the progression of atherosclerosis (AS). The therapeutic potential of reversing EndMT holds promise for AS treatment. In this study, bone marrow mesenchymal stem cells (BMSCs)–derived extracellular vesicles (EVs) are engineered as nanostructured drug carriers with two functional modules, targeting module and functional protein module. In targeting module, to specifically target VECs, the cholesterol-modified aptamers of VECs-specific protein vascular endothelial growth factor (VEGF) are assembled to the engineered EVs. In functional protein module, engineered EVs are infected with recombinant silent information regulator 2–related enzyme 1 (SIRT1) adenoviruses, with the achievement of SIRT1 protein overexpression on the surface. Upon targeted aggregation around the mesenchymalized VECs, the engineered EVs are taken up by VECs and the loaded SIRT1 is released into VECs. Then, SIRT1 can effectively reverse VECs-EndMT by activating nuclear factor-erythroid 2–related factor 2 (Nrf2) and regulating oxidative stress response. The targeted efficacy for precision therapy in AS has been successfully demonstrated both in vitro and in vivo, by reversing EndMT and reducing inflammation in atherosclerotic plaques. This study provides a novel strategy for AS treatment and offers insights into the next generation of regenerative medicine technologies based on engineered EVs.