Extracellular vesicle encapsulated Homer1a as novel nanotherapeutics against intracerebral hemorrhage in a mouse model
Xiaowei Fei, Li Wang, Yanan Dou, Fei Fei, Yanyu Zhang, Weihao Lv, Xin He, Xiuquan Wu, Wangshu Chao, Hongqing Chen, Jialiang Wei, Dakuan Gao, Zhou Fei
Abstract
Abstract Homer1a and A2 astrocytes are involved in the regulation of inflammation induced by intracerebral hemorrhage (ICH). However, there is no anticipated treatment strategy based on the anti-inflammatory effect of Homer1a and A2 astrocytes. Here, we successfully induced A2 astrocytes in vitro, and then we report an efficient method to prepare Homer1a + EVs derived from A2 astrocytes which making it more stable, safe, and targetable to injured neurons. Homer1a + EVs promotes the conversion of A1 to A2 astrocytes in ICH mice. Homer1a + EVs inhibits activation and nuclear translocation of NF-κB, thereby regulating transcription of IL-17A in neurons. Homer1a + EVs inhibits the RAGE/NF-κB/IL-17 signaling pathway and the binding ability of IL-17A: IL17-AR and RAGE: DIAPH1. In addition, Homer1a + EVs ameliorates the pathology, behavior, and survival rate in GFAP Cre Homer1 fl/− Homer1a ± and Nestin Cre RAGE fl/fl ICH mice. Our study provides a novel insight and potential for the clinical translation of Homer1a + EVs in the treatment of ICH.