Extracellular vesicle encapsulated Homer1a as novel nanotherapeutics against intracerebral hemorrhage in a mouse model

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^CreHomer1^fl/-Homer1a^± and Nestin^CreRAGE^fl/fl ICH mice. Our study provides a novel insight and potential for the clinical translation of Homer1a⁺ EVs in the treatment of ICH.

Keywords: A2 astrocyte; Extracellular vehicles; Homer1a; Inflammation; Intracerebral hemorrhage; NF-κB.