Chen Zhuo, Chang Kai, Yang Sha, Deng Ruijia, He Yuan, Zhang Ligai, Chen Ming, Bai Dingqun, Pi Yan
Department of Rehabilitation Medicine, Key Laboratory of Physical Medicine and Precision Rehabilitation of Chongqing Municipal Health Commission, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Clinical Laboratory Medicine, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
J Extracell Vesicles. 2025 Jun;14(6):e70099. doi: 10.1002/jev2.70099.
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.
血管内皮细胞（VECs）的内皮-间充质转化（EndMT）在动脉粥样硬化（AS）进展中起关键作用。逆转EndMT的治疗潜力为AS治疗带来了希望。在本研究中，骨髓间充质干细胞（BMSCs）衍生的细胞外囊泡（EVs）被设计成具有靶向模块和功能蛋白模块两个功能模块的纳米结构药物载体。在靶向模块中，为了特异性靶向VECs，将血管内皮生长因子（VEGF）这种VECs特异性蛋白的胆固醇修饰适配体组装到工程化的EVs上。在功能蛋白模块中，工程化的EVs用重组沉默信息调节因子2相关酶1（SIRT1）腺病毒进行感染，实现SIRT1蛋白在表面的过表达。在间充质化的VECs周围靶向聚集后，工程化的EVs被VECs摄取，负载的SIRT1释放到VECs中。然后，SIRT1可通过激活核因子红细胞2相关因子2（Nrf2）并调节氧化应激反应有效逆转VECs-EndMT。通过逆转EndMT和减轻动脉粥样硬化斑块中的炎症，在体外和体内均成功证明了其对AS精准治疗的靶向疗效。本研究为AS治疗提供了一种新策略，并为基于工程化EVs的下一代再生医学技术提供了见解。
