Restoring Vascular Integrity in Cerebral Aneurysms via IncRNA-eluting Flow Diverter Coating - PROJECT SUMMARY Flow diverters are an established intervention for intracranial aneurysm repair; however, their long-term safety remains limited by thromboembolic complications and delayed aneurysm rupture. These adverse outcomes are partially attributed to incomplete endothelialization of the device and apoptosis of vascular smooth muscle cells, compromising aneurysmal wall integrity. The proposed project aims to develop, evaluate, and two established biomaterials as coatings of flow diverters capable of localized delivery of a long non-coding RNA via polymeric nanoparticles to (i) prevent human brain vascular smooth muscle cells (HBVSMCs) apoptosis while promoting a durable contractile phenotype, and (ii) accelerate endothelialization of the coating surface while supporting an anti-thrombotic, functionally competent endothelial state. Current treatments are effective in diverting flow to create a thrombus within the aneurysmal sac but often fail to restore vascular health at the cellular level, underscoring the need for strategies that support vessel wall recovery. This proposal directly addresses that need by directly altering vascular cell phenotypes via local biomaterial delivery, advancing innovative approaches to aneurysm stabilization and cerebrovascular repair, and therefore treating the burden of cerebrovascular diseases, as highlighted by National Heart, Lung and Blood Institute's objectives to “investigate pathobiological mechanisms important to the onset and progression of heart, lung, and blood diseases and sleep disorders” and “develop and optimize novel diagnostic and therapeutic strategies to prevent, treat, and cure heart, lung, and blood diseases and sleep disorders”[1]. In Aim 1, nanoparticle complexes will be optimized, and their ability to prevent apoptosis and drive the contractile phenotype of HBVSMCs exposed to pro-apoptotic and disturbed-flow conditions will be determined through RT- qPCR, immunofluorescence, enzymatic assays and transcriptomics. Aim 2 will quantify endothelial coverage, junctional integrity, nitric oxide bioavailability, platelet adhesion and transcriptomics of human brain microvascular endothelial cells (HBMECs) cultured on the established coatings to assess the endothelialization rates and anti-thrombotic functions. This project will be conducted within a rigorous research-focused institution and a multidisciplinary vascular bioengineering environment that integrates expertise in biomaterials, vascular biology, and neuroscience. The fellowship training plan emphasizes advanced instruction in endothelial mechanobiology, hemocompatibility assessment, translational biomaterial design and strategies for clinical translation, providing the applicant with a strong foundation for an independent research career in cerebrovascular regenerative biomedicine, as well as the goal of attaining tenure-track professorship. 1. National Heart, Lung, and Blood Institute (NHLBI). The NHLBI Strategic Vision: FY 2026–2030. National Institutes of Health, 2025. NIH Publication 25-HL-6150.
