Astrocyte-Derived Exosomal miR-211-5p Alleviates Blood-Brain Barrier Injury in a Rat Model of Traumatic Brain Injury.

Abstract

BACKGROUND: Traumatic brain injury (TBI) triggers a cascade of secondary damage, including neuroinflammation, astrocyte activation, and disruption of the blood-brain barrier (BBB), all of which contribute to long-term neurological deficits. Astrocyte-derived exosomes have emerged as a promising therapeutic avenue; however, the specific contributions of their molecular cargo remain poorly understood. This study explores whether astrocyte-derived exosomal delivery of microRNA-211-5p (miR-211-5p) can attenuate secondary injury and enhance functional recovery following TBI. METHODS: Primary astrocytes were transfected with AAV-rno-miR-211-5p, and the resulting exosomes were isolated and characterized. TBI was induced in adult rats using a controlled cortical impact (CCI) model. Exosomes (1 × 10particles) were administered intravenously 30 min post-injury. Behavioral assessments were conducted to evaluate cognitive function and neurological deficits. Brain edema, glial activation, and the expression of inflammatory cytokines (IL-6, IL-1β, TNF-α) and BBB-related markers-including glial fibrillary acidic protein (GFAP), matrix metalloproteinase 9 (MMP9), aquaporin 4 (AQP4), and the tight junction proteins zonula occludens-1 (ZO-1) and claudin-5-were analyzed using quantitative real-time PCR, Western blotting, enzyme-linked immunosorbent assay, and histopathological techniques. RESULTS: Exosomes enriched with miR-211-5p significantly improved cognitive and neurological outcomes, reduced cerebral edema, and downregulated the expression of GFAP, MMP9, and AQP4. Furthermore, the integrity of the BBB was preserved, as evidenced by sustained expression of ZO-1 and claudin-5. Levels of the proinflammatory cytokines IL-6, IL-1β, and TNF-α were also markedly decreased in the injured cortex. CONCLUSION: Astrocyte-derived exosomal miR-211-5p confers neuroprotection in TBI by modulating glial activation, reducing neuroinflammation, and preserving BBB integrity. These findings underscore the therapeutic potential of miR-211-5p-loaded exosomes as a cell-free, targeted intervention for brain trauma.