Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 39, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2201443119
Keywords
nanomedicine; atherosclerosis; nucleic acid nanotechnology; gene therapy; cardiovascular disease
Categories
Funding
- Research Grants Council [14300120, 14109519, 14105321]
- Chow Yuk Ho Technology Centre for Innovative Medicine
- National Nature Science Foundation of China [81922078]
- Croucher Innovation Award from the Croucher Foundation
- Vice Chancellor Discretionary Fund at CUHK
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This study demonstrates the use of a three-dimensional nanostructure for delivering therapeutic oligonucleotides to atherosclerotic plaques. The nanoparticles target specific cells in the plaques and modulate genes related to plaque formation and inflammation, resulting in reduced and stabilized plaques without severe toxicity.
Atherosclerosis treatments by gene regulation are garnering attention, yet delivery of gene cargoes to atherosclerotic plaques remains inefficient. Here, we demonstrate that assembly of therapeutic oligonucleotides into a three-dimensional spherical nucleic acid nanostructure improves their systemic delivery to the plaque and the treatment of atherosclerosis. This noncationic nanoparticle contains a shell of microRNA-146a oligonucleotides, which regulate the NF-kappa B pathway, for achieving transfection-free cellular entry. Upon an intravenous injection into apolipoprotein E knockout mice fed with a high-cholesterol diet, this nanoparticle naturally targets class A scavenger receptor on plaque macrophages and endothelial cells, contributing to elevated delivery to the plaques (similar to 1.2% of the injected dose). Repeated injections of the nanoparticle modulate genes related to immune response and vascular inflammation, leading to reduced and stabilized plaques but without inducing severe toxicity. Our nanoparticle offers a safe and effective treatment of atherosclerosis and reveals the promise of nucleic acid nanotechnology for cardiovascular disease.
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