期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2021
卷号：118
期号：50
DOI：10.1073/pnas.2114842118
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Vascular disease is a leading cause of human morbidity and mortality and current therapies mainly target systemic risk factors but not the diseased vasculature per se. We have devised a targeted nanomedicine approach engineering self-assembled polyelectrolyte complex micelles that target inflamed vascular endothelium and simultaneously encapsulate therapeutic nucleic acids. We showed that this targeted nanomedicine strategy effectively delivers therapeutic nucleotides to inflamed endothelium in vivo. The causal role of increased endothelial miR-92a in driving atherosclerosis is established by a new transgenic mouse line. We demonstrated that targeted polyelectrolyte complex micelles significantly enhance the anti–miR-92a therapy treating vascular complications in vivo.
Vascular disease is a leading cause of morbidity and mortality in the United States and globally. Pathological vascular remodeling, such as atherosclerosis and stenosis, largely develop at arterial sites of curvature, branching, and bifurcation, where disturbed blood flow activates vascular endothelium. Current pharmacological treatments of vascular complications principally target systemic risk factors. Improvements are needed. We previously devised a targeted polyelectrolyte complex micelle to deliver therapeutic nucleotides to inflamed endothelium in vitro by displaying the peptide VHPKQHR targeting vascular cell adhesion molecule 1 (VCAM-1) on the periphery of the micelle. This paper explores whether this targeted nanomedicine strategy effectively treats vascular complications in vivo. Disturbed flow-induced microRNA-92a (miR-92a) has been linked to endothelial dysfunction. We have engineered a transgenic line (
miR-92a
EC-TG
/
Apoe
−/−
) establishing that selective miR-92a overexpression in adult vascular endothelium causally promotes atherosclerosis in
Apoe
−/−
mice. We tested the therapeutic effectiveness of the VCAM-1–targeting polyelectrolyte complex micelles to deliver miR-92a inhibitors and treat pathological vascular remodeling in vivo. VCAM-1–targeting micelles preferentially delivered miRNA inhibitors to inflamed endothelial cells in vitro and in vivo. The therapeutic effectiveness of anti–miR-92a therapy in treating atherosclerosis and stenosis in
Apoe
−/−
mice is markedly enhanced by the VCAM-1–targeting polyelectrolyte complex micelles. These results demonstrate a proof of concept to devise polyelectrolyte complex micelle-based targeted nanomedicine approaches treating vascular complications in vivo.
