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This study aims to elucidate how bone marrow stromal cell-derived exosome (BMSC-exo) influence BBB injury and HT and the related molecular mechanisms, focusing on the core function of exosome miR-21a-5p. The HT model induced by middle cerebral artery occlusion (MCAO-HT) was treated with tail vein injection of BMSCs-exo, and HT, BBB injury and brain damage were assessed by mNSS score, triphenyltetrazolium chloride (TTC) staining, evan\u2019s blue (EB)\/hemoglobin leakage assay, and HE staining. High abundance miRNAs in BMSC-exo were identified by Small RNA sequence. BMSC-exo miR-21a-5p was modulated using inhibitor and mimic, following by exploring the function of miR-21a-5p in an MCAO-HT animal model and an BBB model. BMSCs-exo effectively enhanced neurological recovery, minimized infarct size, mitigated BBB leakage, and upregulated the expression of Claudin-5\/Occludin\/ZO-1 in the MCAO-HT model. Five hundred and seventy-one miRNAs were identified in BMSCs-exo, and the targets of the TOP 10 miRNAs in abundance were enriched in TLR, NF-\u03baB, and MMPs pathways. In in vitro experiments, BMSCs-exo rescued oxygen glucose deprivation\/reperfusion-induced BBB injury by delivering miR-21a-5p, characterized by an increase in trans epithellal electric resistance and tight junction protein levels and a decrease in permeability, which was dependent on the inhibition of TLR2\/NF-\u03baB pathway and the levels and enzymatic activities of MMP2\/9. In in vivo experiments, miR-21a-5p knockdown impaired the neuroprotective effects of BMSCs-exo, whereas miR-21a-5p overexpressing lentivirus alone significantly ameliorated brain injury and inhibited the TLR2\/NF-\u03baB pathway and the levels and enzymatic activities of MMP2\/9 in the MCAO-HT model. BMSCs-exo mitigates BBB disruption and HT by delivering miR-21a-5p to inhibit the TLR2\/NF-\u03baB pathway, downregulate the levels and enzymatic activities of MMP-2\/9 and protect tight junction proteins.<\/jats:p>","DOI":"10.1007\/s12035-025-05650-6","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T08:21:25Z","timestamp":1767860485000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["BMSC-Derived Exosomal miR-21a-5p Ameliorates Blood\u2013Brain Barrier Injury and Hemorrhagic Transformation"],"prefix":"10.1007","volume":"63","author":[{"given":"Jing","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruanxian","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaojiao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengwen","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,8]]},"reference":[{"key":"5650_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241814067","author":"KB Kov\u00e1cs","year":"2023","unstructured":"Kov\u00e1cs KB, Bencs V, Hud\u00e1k L et al (2023) Hemorrhagic transformation of ischemic strokes. 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