The blockage of blood vessels caused by atherosclerosis is a leading cause of stroke and ischemic heart disease. However, current treatments including surgery are invasive, while lipid-lowering drugs can only slow down disease progression. While gene regulation is an emerging therapeutic approach to atherosclerosis, the delivery of therapeutic gene cargoes to atherosclerotic plaques remains inefficient.
A team led by Professor Jonathan Choi Chung-hang, Associate Professor in the Faculty of Engineering’s Department of Biomedical Engineering at The Chinese University of Hong Kong (CUHK), has developed a novel RNA nanoparticle to offer a potentially safe, effective treatment for atherosclerosis.
Research has shown that this RNA nanoparticle can naturally target receptors of plaque cells for delivering genes to atherosclerotic plaques, while alleviating atherosclerosis by modulating genes related to atherogenesis, consequently reducing and stabilising plaque without inducing severe toxicity. It paves the way for the use of nucleic acid nanotechnology to treat cardiovascular diseases.
The research, a collaboration with Professor Tian Xiao-yu, Assistant Professor in the Faculty of Medicine’s School of Biomedical Sciences at CUHK, has recently been published in the international journal The Proceedings of the National Academy of Sciences (PNAS).
Limitations of existing treatments
Atherosclerosis is a form of chronic inflammation caused primarily by high blood lipid levels. Fat, cholesterol and immune cell build-ups on the arterial wall induce the formation of atherosclerotic plaques. These plaques either narrow the blood vessels, restricting blood flow or they burst, forming blood clots that block thinner arteries in the brain or heart. This can lead to a stroke or ischemic heart disease.
World Health Organisation (WHO) research shows that stroke and ischemic heart disease accounted for 11% and 16% respectively of global mortality in 2020. In Hong Kong, heart disease has been the third-leading cause of death since the 1960s.
While treatment does exist for atherosclerosis (it includes surgical procedures like balloon angioplasty and endarterectomy), they are invasive and inefficient in reducing multiple plaque sites. Administering lipid-lowering drugs such as statins is also a treatment, but they can only slow down disease progression.
Bypassing the bottleneck for gene delivery with nucleic acid nanotechnology
Gene regulation is an emerging therapeutic approach to atherosclerosis, but current technology for gene delivery to plaque remains inefficient. Existing atherosclerosis nanomedicines mostly employ cationic carriers to complex gene cargoes through electrostatic interactions for gene delivery into plaque cells.
However, these nanomedicines are often bulky, larger than 100 nm, meaning they can be rapidly filtered by the liver and spleen following an intravenous injection before they reach the plaque, and they are cationic which may induce cytotoxicity in the body.
By passing this bottleneck in gene delivery, the CUHK has applied nucleic acid nanotechnology to develop a new RNA nanoparticle for plaque delivery. This smaller spherical nanoparticle of about 70 nm in size includes a biocompatible iron oxide nanoparticle core and about 300 therapeutic microRNA-146a strands attached to the core’s surface.
Their solution can naturally enter plaque cells without the aid of cationic transfection agents, thereby facilitating the intracellular delivery of microRNA-146a.
Data from the experiments have shown that upon an intravenous injection into mice that bear atherosclerotic plaques, the new RNA nanoparticle can naturally target the receptors on plaque cells and preferentially enter macrophages and endothelial cells inside the plaque.
Alleviating atherosclerosis with intravenous injections of RNA nanostructures
Furthermore, experiments have shown that repeated injections of RNA nanoparticles into plaque-bearing mouse models not only regressed and stabilised atherosclerotic plaque but also downregulated genes related to immune response and vascular inflammation. After four weeks of treatment, there was no pronounced accumulation of RNA nanoparticles inside major internal organs, nor did it induce severe toxicity.
