Extracellular vesicles from neural stem cells safeguard neurons in intracerebral hemorrhage by suppressing reactive astrocyte neurotoxicity.

Extracellular vesicles (EVs) derived from stem cells have shown therapeutic potential in various diseases, but their use in treating neurological disorders remains limited. In this study, we observed neurotoxic activation of reactive astrocytes and lipoapoptosis pathways in both mice and patients with intracerebral hemorrhage (ICH) and found that EVs derived from neural stem cells (EVs-NSC) could suppress this activation. Using loss- and gain-of-function approaches, we identified interferon-β (IFNβ) as a key regulator in neurotoxic activation of astrocytes. In addition, we demonstrated that the microRNA (miRNA) miR-124-3p within EVs-NSC degrades IFNβ mRNA and inhibits ELOVL1 expression via miRNA-coding sequence (CDS) and miRNA-3' UTR binding mechanisms, respectively. This dual action likely reduces astrocyte neurotoxicity by lowering saturated lipid secretion. These mechanisms enable EVs-NSC or miR-124-3p overexpression to inhibit astrocyte neurotoxicity, reduce neural damage, and promote recovery in ICH models, offering strategies for treating neurological disorders by targeting neurotoxic reactive astrocytes.