Edaravone delivery of exosome-liposome hybrid nanoparticles for the treatment of ischemic stroke.

Ischemic stroke (IS) triggers neuroinflammatory cascades mediated by microglial polarization, where pro-inflammatory M1 phenotypes exacerbate neuronal damage, and anti-inflammatory M2 phenotypes promote repair. Edaravone (Eda), a free radical scavenger, shows potential for modulating microglial polarization but faces challenges in penetrating the blood-brain barrier (BBB) and achieving targeted delivery. This study develops a hybrid nanoparticle (SHp-NSCsome) that integrates hypoxia-preconditioned neural stem cell-derived exosomes with Eda-loaded liposomes functionalized with the ischemic-homing peptide SHp. SHp-NSCsome combines the biocompatibility and immunomodulatory properties of exosomes with the drug-loading capacity of liposomes, enabling efficient BBB traversal and targeting of ischemic lesions. In vitro analyses demonstrated the superior anti-apoptotic effects, mitochondrial protection, and M2 polarization of microglia by SHp-NSCs under oxygen-glucose deprivation, significantly reducing pro-inflammatory cytokines while enhancing anti-inflammatory mediators. In vivo studies involving mice subjected to middle cerebral artery occlusion (MCAO) indicated a significant accumulation of SHp-NSCsome within ischemic areas, leading to a decrease in infarct size and improvement in neurological function. Mechanistically, SHp-NSCsome regulates microglial polarization by inhibiting the glycolysis pathway mediated by HIF-1α. These dual-functional nanoparticles synergize antioxidant and immunoregulatory actions, offering a promising therapeutic strategy for IS by precisely modulating post-ischemic neuroinflammation.