Bioinspired VasculoGenic-NanoVesicle: A dual-targeted therapeutic platform for ischemic stroke through vascular remodeling and anti-inflammation

Therapeutic strategies for cerebral ischemic stroke face critical challenges in mitigating secondary cerebrovascular injury following recanalization. In this study, we engineered interleukin-4-functionalized VasculoGenic-NanoVesicles (IL4@SDNVs) that exhibit tripartite therapeutic efficacy: preserving blood-brain barrier integrity, suppressing neuroinflammatory cascades, specifically microglial pro-inflammatory polarization and peripheral immune cell infiltration, and inducing EMCN⁺/CD31⁺ vascular neogenesis and achieving 144.1% increase in cerebral blood perfusion within the ischemic hemisphere in a mouse middle cerebral artery occlusion (MCAO) model. Mechanistically, post-recanalization administration of IL4@SDNV selectively promoted arginase-1⁺ (Arg1⁺) microglial polarization in the ischemic penumbra via the IL4-STAT6 signaling pathway, thereby exerting neuroprotection and cerebrovascular remodeling. Collectively, our findings demonstrate that IL4@SDNV as a promising adjuvant therapy for ischemic stroke post-recanalization through addressing cerebrovascular pathology and neuroinflammation simultaneously, thus highlighting its translational potential for clinical application.