Abstract: The blood–brain barrier (BBB), a highly specialized neurovascular structure indispensable for preserving cerebral homeostasis, exhibits significant impairment across diverse neurological pathologies; however, its therapeutic targeting persists as a formidable challenge due to the inherent complexity of its multicellular architecture and dynamic regulatory networks. Although the Wnt/β-catenin signaling pathway orchestrates the development and maintenance of the BBB, the clinical translation of Wnt-based interventions remains elusive. To overcome these limitations, we engineered a neural stem cell-derived extracellular vesicle (EVs-NSC) platform functionalized with Wnt7a-K190A—an engineered BBB-tropic ligand (designated EVs-WK). In vitro mechanistic studies demonstrated that EVs-WK had three main effects: they enhanced BBB integrity, promoted synaptogenesis through β-catenin-mediated reinforcement, and suppressed neurotoxic activation of astrocytes by preserving EV-embedded miR-124-3p. In murine intracerebral hemorrhage (ICH) models, administering EVs-WK significantly reduced hematoma expansion and accelerated motor recovery. Cross-species validation using humanized EVs (hEVs-WK) confirmed the conserved therapeutic efficacy of this approach, as shown by the mitigation of LPS-induced barrier dysfunction and downregulation of inflammatory pathways. Overall, this modular EV platform combines BBB restoration with neurovascular unit repair, thus overcoming critical translational barriers in neurological therapeutics through targeted-controlled activation of Wnt signaling.
Funding Source: This work was supported by grants from the Ministry of Science and Technology of China (2018YFA0107900, 92168103, 32171417, 82001140, 2019CXJQ01, 2023TQ0072, and 2023M740676), the National Natural Science Foundation of China.
