Ischemic stroke remains a leading cause of death and disability in the United States. Although interventions such as tissue plasminogen activator and mechanical thrombectomy have improved acute outcomes, many patients experience long-term deficits due to secondary ischemia-reperfusion injury. Blood-brain barrier (BBB) disruption, particularly via increased endothelial transcytosis, is a key pathological contributor to these outcomes. Our RNA-seq analysis at 24 hours post-transient middle cerebral artery occlusion (tMCAO) revealed increased expression of caveolin-1 and decreased β-catenin levels, changes associated with enhanced vesicular transcytosis and BBB breakdown compared to sham controls. These findings identify Major Facilitator Superfamily Domain Containing 2a (MFSD2A) as a critical modulator of BBB integrity, as MFSD2A inhibits caveolin-1–mediated transcytosis and is positively regulated by β-catenin signaling. Targeted nanoparticle delivery offers a promising strategy to improve therapeutic specificity in brain diseases, including ischemic stroke. Vascular cell adhesion molecule (VCAM), upregulated during neuroinflammation, serves as an effective target for drug delivery to ischemic vasculature. Our laboratory demonstrated that VCAM-targeted lipid nanoparticles (LNPs) significantly increased brain accumulation of mRNA cargo versus non-targeted controls in multiple disease models, including tMCAO. In this study, we developed VCAM-targeted LNPs encapsulating MFSD2A mRNA (VCAM/MFSD2A) to 1) selectively deliver therapeutics to inflamed cerebral endothelium and 2) restore BBB function. In vitro, VCAM/MFSD2A treatment of bEnd3 cells significantly reduced surface pits indicative of transcytosis inhibition versus untreated cells. In vivo, VCAM/MFSD2A-treated tMCAO mice showed a ~22% increase in survival compared to untreated controls and significantly better survival than the non-targeted IgG/MFSD2A group, which exhibited 40% survival at study end. Treated mice also demonstrated improved neurobehavioral scores on days 1–3 post-stroke. BBB integrity was preserved, as shown by reduced radiolabeled albumin extravasation, and electron microscopy confirmed decreased endothelial caveolae in treated animals. Collectively, these results demonstrate that VCAM/MFSD2A effectively mitigates stroke-induced BBB dysfunction, reduces cerebral edema, and improves neurological recovery. This approach represents a promising therapeutic strategy for enhancing stroke outcomes.
Jeong et al. (Thu,) studied this question.