Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, China.
CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
Biomaterials. 2025 Mar;314:122832. doi: 10.1016/j.biomaterials.2024.122832. Epub 2024 Sep 11.
Extracellular vesicles (EVs) secreted by endothelial cells in response to blood laminar flow play a crucial role in maintaining vascular homeostasis. However, the potential of these EVs to modulate the immune microenvironment within plaques for treating atherosclerosis remains unclear. Here, we present compelling evidence that EVs secreted by endothelial cells sheared by atheroprotective laminar shear stress (LSS-EVs) exhibit excellent immunoregulatory effects against atherosclerosis. LSS-EVs demonstrated a robust capacity to induce the conversion of M1-type macrophages into M2-type macrophages. Mechanistic investigations confirmed that LSS-EVs were enriched in miR-34c-5p and reprogrammed macrophages by targeting the TGF-β-Smad3 signaling pathway. Moreover, we employed click chemistry to modify hyaluronic acid (HA) on the surface of LSS-EVs, enabling specific binding to the CD44 receptor expressed by inflammatory macrophages within plaques. These HA-modified LSS-EVs (HA@LSS-EVs) exhibited exceptional abilities for targeting atherosclerosis and demonstrated promising therapeutic effects both in vitro and in vivo.
内皮细胞在应对血流层流时分泌的细胞外囊泡（EVs）在维持血管稳态方面发挥着关键作用。然而，这些 EVs 调节斑块内免疫微环境以治疗动脉粥样硬化的潜力尚不清楚。在这里，我们提供了令人信服的证据，表明在抗动脉粥样硬化的层流剪切应力（LSS-EVs）下剪切的内皮细胞分泌的 EVs 对动脉粥样硬化具有出色的免疫调节作用。LSS-EVs 表现出强大的能力，可以诱导 M1 型巨噬细胞向 M2 型巨噬细胞转化。机制研究证实，LSS-EVs 富含 miR-34c-5p，并通过靶向 TGF-β-Smad3 信号通路重新编程巨噬细胞。此外，我们采用点击化学在 LSS-EVs 表面修饰透明质酸（HA），使其能够与斑块内炎症巨噬细胞表达的 CD44 受体特异性结合。这些经过 HA 修饰的 LSS-EVs（HA@LSS-EVs）具有针对动脉粥样硬化的出色靶向能力，并在体外和体内均显示出有前途的治疗效果。
