Tailored Apoptotic Vesicle Delivery Platform for Inflammatory Regulation and Tissue Repair to Ameliorate Ischemic Stroke

作者：Yang You, Jianpei Xu, Yipu Liu, Haichun Li, Laozhi Xie, Chuchu Ma, Yinzhe Sun, Shiqiang Tong, Kaifan Liang, Songlei Zhou, Fenfen Ma, Qingxiang Song, Wenze Xiao, Kaikai Fu, Chengxiang Dai, Suke Li, Jigang Lei, Qiyong Mei, Xiaoling Gao, Jun Chen · 发表于：ACS Nano · 年份：2023 · DOI：10.1021/acsnano.3c01497 · 被引用次数：80 · 研究领域：Extracellular vesicles in disease、RNA Interference and Gene Delivery、Phagocytosis and Immune Regulation

Apoptotic vesicles (ApoVs) hold great promise for inflammatory regulation and tissue repair. However, little effort has been dedicated to developing ApoV-based drug delivery platforms, while the insufficient targeting capability of ApoVs also limits their clinical applications. This work presents a platform architecture that integrates apoptosis induction, drug loading, and functionalized proteome regulation, followed by targeting modification, enabling the creation of an apoptotic vesicle delivery system to treat ischemic stroke. Briefly, α-mangostin (α-M) was utilized to induce mesenchymal stem cell (MSC) apoptosis while being loaded onto MSC-derived ApoVs as an anti-oxidant and anti-inflammatory agent for cerebral ischemia/reperfusion injury. Matrix metalloproteinase activatable cell-penetrating peptide (MAP), a microenvironment-responsive targeting peptide, was modified on the surface of ApoVs to obtain the MAP-functionalized α-M-loaded ApoVs. Such engineered ApoVs targeted the injured ischemic brain after systemic injection and achieved an enhanced neuroprotective activity due to the synergistic effect of ApoVs and α-M. The internal protein payloads of ApoVs, upon α-M activation, were found engaged in regulating immunological response, angiogenesis, and cell proliferation, all of which contributed to the therapeutic effects of ApoVs. The findings provide a universal framework for creating ApoV-based therapeutic drug delivery systems for the amelioration of inflammatory d...