Intranasal Delivery of Dental Stem-Cell-Derived Extracellular Vesicles Improves Blood–Brain Barrier Integrity Following Ischemic Stroke by Alleviating Oxidative Stress

Ischemic stroke is a debilitating neurovascular condition characterized by a focal disruption of the cerebral blood supply. Current clinical interventions have been developed to restore the cerebral circulation; however, functional recovery from neurological injury remains unsatisfactory. Extracellular vesicles derived from mesenchymal stem cells are prominent therapeutic agents for neurological diseases. Notably, extracellular vesicles derived from dental stem cells (DSC-EVs) are considered promising because of their developmental similarity to the neural crest. In rat models of ischemic stroke, intranasally administered DSC-EVs exerted more significant therapeutic efficacy compared to extracellular vesicles derived from bone marrow and adipose tissue sources. This non-invasive intranasal route increased detectable brain-associated fluorescence without the need for systemic injections. Functionally, DSC-EVs improved neurological recovery by reducing infarct size and restoring blood–brain barrier integrity. Mechanistically, DSC-EVs, enriched in miR-21-5p, attenuated oxidative stress in cerebral microvascular endothelial cells, potentially involving the downregulation of S100A10 expression and thereby preserving tight junction integrity. Our findings reveal the distinguishing therapeutic potential of DSC-EVs in ischemic stroke and suggest a mechanism by which intranasally delivered DSC-EVs alleviate ischemia–reperfusion-induced blood–brain barrier disruption through the modulation of S100A10-associated endothelial oxidative stress, supporting further preclinical evaluation of DSC-EVs as a non-invasive approach for post-stroke neurovascular repair.