Developing unique anti-EndMT nanoparticle therapy for cardiovascular disease

About This Grant

PROJECT SUMMARY Vascular diseases driven by endothelial dysfunction represent a major therapeutic challenge due to the lack of cell-specific delivery systems. While TGFβ-driven endothelial-to-mesenchymal transition (EndMT) has emerged as a key therapeutic target, current approaches are limited by off-target effects of systemic TGFβ inhibition. We have developed a novel HDL-mediated RNA delivery platform (C15-9- 900 LNP) that achieves unprecedented endothelial cell specificity through innovative ionizable lipid design. Our preliminary data demonstrate >90% targeting efficiency across multiple vascular beds, with exceptional manufacturing reproducibility at 2g scale, minimal inflammatory response, and established quality control parameters. This R21 ASCETTS proposal will advance platform development through two complementary aims. In Aim 1, we will establish critical quality attributes and manufacturing parameters through systematic evaluation of formulation conditions. Comprehensive particle characterization will include size, polydispersity index, and zeta potential analysis, complemented by quantitative biodistribution studies using endothelial lineage-traced mice. Advanced imaging and flow cytometry validation will confirm targeting specificity across multiple vascular beds. In Aim 2, we will demonstrate therapeutic efficacy using an established hypoxia- induced pulmonary hypertension model. We will evaluate the platform's ability to modulate TGFβ pathway signaling in pulmonary vascular endothelium, assess therapeutic outcomes through comprehensive hemodynamic and histological analyses, and establish clear translational parameters for clinical development. This platform technology represents a fundamental advance in targeted RNA therapeutics by enabling selective endothelial modification while minimizing systemic effects. Our systematic approach establishes standardized manufacturing parameters and analytical methods suitable for clinical translation. While initially focused on pulmonary hypertension, the platform creates a foundation for addressing multiple cardiovascular disorders where endothelial dysfunction plays a central role. Success in this R21 phase will accelerate therapeutic innovation through validated manufacturing processes and clear regulatory parameters.