Abstract WP340: From Neurovascular Challenge to Therapeutic Opportunity: VCAM-Targeted Nanocarriers in Acute Ischemic Stroke and Intracranial Hemorrhage

Acute neurovascular diseases such as ischemic stroke (AIS) and intracerebral hemorrhage (ICH) remain leading causes of mortality and disability. Both are fueled by neuroinflammation and blood-brain barrier (BBB) disruption, which challenge effective brain drug delivery and limit current therapeutic impact. We have developed VCAM-targeted nanocarriers (T-NCs) that leverage vascular cell adhesion molecule-1 upregulation at the inflamed BBB, achieving highly selective targeting: 20-fold higher uptake by BBB endothelial cells over untargeted controls and up to 100-fold compared to free drugs, surpassing transferrin receptor-targeted approaches by 15-fold. In AIS models, VCAM T-NCs delivered small molecules (dexamethasone and fingolimod), proteins, and mRNAs (luciferase, Cre-recombinase, IL-10, Mfsd2A, tight junction components, and thrombomodulin) directly to the BBB endothelium in affected regions. This strategy produced marked reductions in brain inflammation, cerebral edema, and infarct volume (by up to 65%), and improved survival rates with mRNA/IL-10 cargo. Critical mechanistic benefits included enhancing BBB homeostasis, suppressing caveolar transcytosis, and reinforcing junctional integrity. Notably, VCAM T-NCs transformed the brain vasculature into a depot for sustained drug release and a “biofactory” for proteins via endothelial transfection—spatial and functional distribution confirmed by mass spectrometry and CLARITY imaging in AIS. Mechanistically, AIS treatment led to an approximately 75% reduction in macrophage infiltration in the injured hemisphere. In ICH, current treatments remain mostly supportive, and effective disease-targeted therapies are lacking. VCAM T-NCs loaded with IL-10 mRNA selectively targeted the inflamed endothelium of the hemorrhagic brain, resulting in significant reductions in hematoma volume and robust improvements in motor function. Distinct from AIS, VCAM T-NC therapy in ICH did not merely decrease macrophage counts but shifted their phenotype, promoting neuroprotective M2 polarization, as confirmed by molecular and behavioral analyses. Thus, VCAM-targeted nanocarriers represent a versatile, mechanism-tailored platform for neurovascular drug delivery. They enable precision interventions in AIS via selective BBB targeting, suppression of inflammation, and reduced immune cell infiltration, while in ICH, they mediate immunomodulatory phenotype shifts among macrophages for tissue protection and recovery.