Precision Nanomedicine Targeting Novel Endothelial Mechano-Sensing Mechanisms and Treating Vascular Complications in vivo

ABSTRACT

Introduction: Endothelial mechano-transduction mechanisms are instrumental to vascular health and disease. Novel strategies targeting disease-causing mechano-sensitive pathways in dysfunctional endothelial cells could revolutionize future cardiovascular therapeutics. Vascular complications such as atherosclerosis and stenosis preferentially develop at arterial curvatures and bifurcations where endothelial cells are activated by local disturbed blood flow, leading to peripheral artery disease, carotid artery disease and ischemic stroke. Hypothesis: Current vascular therapies mainly target systematic risk factors (e.g. hypercholesterolemia and hypertension) but not the diseased vasculature, distinct molecular/cellular signatures of which can be targeted by innovated precision nanomedicine approaches. Method(s) We first elucidated novel mechano-sensitive molecular mechanisms in endothelium activated by disturbed flow (DF) and then engineered rationally-designed nano-materials with purposed-constructed functionalities to deliver therapeutic nucleotides to DF-activated endothelial cells. Result(s) Our results elucidated previously unrecognized endothelial mechano-sensitive pathways in endothelial activation, with emphasis upon cellular metabolism (DF-induced glycolysis), human genetic variants (DF-induced suppression of PLPP3, a CAD GWAS gene), miRNA, protein stability (DF-induced NOS3 protein degradation via TXNDC5) and mRNA chemical modification/epitranscriptome (DF-induced suppression of m7G). VCAM1-targeting nanoparticles were engineered to deliver therapeutic nucleotides such as mRNA, miRNA inhibitor, or CRISPR/Cas9 constructs specifically to inflamed endothelial cells to intervene aforementioned mechano-sensitive pathways, effectively reducing atherosclerosis and stenosis in mice. Similar approaches were very effective to promote endothelial health and lessen acute respiratory distress syndrome (ARDS) in mice induced by influenza or SARS-CoV-2 viruses. Conclusion(s) These results elucidate novel endothelial mechano-sensing mechanisms and provide a proof of concept of innovative targeted nanomedicine approaches, addressing an unmet medical need in vascular therapies.