Key Laboratory for Advanced Technologies of Materials, Ministry of Education, School of Material Science and Engineering, Southwest Jiaotong University, Chengdu 610031, P.R. China.
ACS Nano. 2022 Sep 27;16(9):14925-14941. doi: 10.1021/acsnano.2c05847. Epub 2022 Sep 6.
The efferocytosis defect is regarded as a pivotal event of atherosclerosis. The failure to clear apoptotic cells in atherosclerotic plaques under vascular stents causes a failure to resolve the inflammation underneath. However, efferocytosis repair is still confined to nonstenting therapeutics. Here, we identified a pro-efferocytotic agent and accordingly developed a bioresponsive pro-efferocytotic vascular stent aimed for poststenting healing. Exosomes derived from mesenchymal stem cells were found to be able to regulate efferocytosis SLC2a1, STAT3/RAC1, and CD300a pathways and modulate foam cell formation processes through a CD36-mediated pathway. Pro-efferocytotic exosomes were encapsulated into liposome-based multivesicular chambers and grafted onto vascular stents. The multivesicular vesicles were able to release exosomes under the Lp-PLA environment. Compared to bare metal stents, exosome-stents in the presence of Lp-PLA enhanced the ratio of apoptotic cell clearance and reduced the neointimal thickness in the mal-efferocytotic rat model. Overall, we identified a pro-efferocytic agent─exosomes that are able to regulate target cells multiple signaling pathways and are good candidates to serve complex pathological environments, and this bioresponsive pro-efferocytotic vascular stent is an attractive approach for prevention of poststenting complications.
噬作用缺陷被认为是动脉粥样硬化的关键事件。血管支架下斑块中凋亡细胞的清除失败导致炎症在支架下无法消退。然而，噬作用的修复仍然局限于非支架治疗。在这里，我们鉴定了一种促噬作用的药物，并据此开发了一种生物响应性的促噬作用血管支架，用于支架后愈合。间充质干细胞衍生的外体被发现能够调节噬作用 SLC2a1、STAT3/RAC1 和 CD300a 途径，并通过 CD36 介导的途径调节泡沫细胞形成过程。促噬作用的外体被包裹在基于脂质体的多泡室中，并嫁接到血管支架上。多泡囊在 Lp-PLA 环境下能够释放外体。与裸金属支架相比，存在 Lp-PLA 的外体支架增强了凋亡细胞清除率的比值，并减少了易噬作用大鼠模型中的新生内膜厚度。总的来说，我们鉴定了一种促噬作用的药物——外体，它能够调节靶细胞的多种信号通路，是用于复杂病理环境的良好候选药物，这种生物响应性的促噬作用血管支架是预防支架后并发症的一种有吸引力的方法。
