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Using an unbiased anti-miR lentiviral screen, miR-23b was identified as a critical negative regulator of BBB integrity in brain endothelial cells (BECs). Targeted inhibition of miR-23b using anti-miR-23b, validated by Wnt-reporter, Wnt-rescue, and eCLIP analysis, demonstrates that BEC miR-23b silencing in BECs, enhances junctional protein expression and strengthens barrier function while suppressing transcellular transport. Global multi-omics analysis reveals that miR-23b acts as a robust driver of angiogenesis-specific genes and proteins. Conversely, anti-miR-23b induces the expression of factors essential for BBB stabilization and repair. Notably, anti-miR-23b enhances these protective barrier properties through the multi-faceted regulation of Wnt\/\u03b2-catenin, TGF-\u03b2, Notch, and VEGF signaling mechanisms. Using a 3D microfluidic platform, anti-miR-23b was shown to foster BBB repair by accelerating vessel maturation and enhancing resilience against ischemic injury. Proof-of-concept studies show that BEC specific AAVBR1-anti-miR-23b gene therapy reinforces BBB tight junctions, reduces BBB leakage, and improves outcome measures in a transient middle cerebral artery occlusion (t-MCAO) stroke model. Thus, miR-23b is a critical regulator of cerebrovascular integrity, positioning anti-miR-23b as a promising RNA-based therapy to enhance BBB stability and repair in stroke and other CNS disorders.<\/jats:p>","DOI":"10.1101\/2025.08.20.671398","type":"posted-content","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T16:00:14Z","timestamp":1756137614000},"source":"Crossref","is-referenced-by-count":0,"title":["Modulation of miR-23b Wnt\/\u03b2-catenin Axis Strengthens Endothelial Barrier Properties"],"prefix":"10.64898","author":[{"given":"Victor Anthony","family":"Martinez","sequence":"first","affiliation":[{"name":"Scintillon Aging Research Center, Scintillon Research Institute, San Diego, CA 92121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6506-2822","authenticated-orcid":false,"given":"Rose","family":"Presby","sequence":"additional","affiliation":[{"name":"Scintillon Aging Research Center, Scintillon Research 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