Modulating Plaque Inflammation <i>via</i> Targeted mRNA Nanoparticles for the Treatment of Atherosclerosis.

Abstract

Atherosclerosis is a common pathology present in many cardiovascular diseases. Although the current therapies (including statins and inhibitors of the serine protease PCSK9) can effectively reduce low-density lipoprotein (LDL) cholesterol levels to guideline-recommended levels, major adverse cardiovascular events still occur frequently. Indeed, the subendothelial retention of lipoproteins in the artery wall triggers multiple events of inflammation in macrophages and is a major contributor to the pathological progression of atherosclerosis. It has been gradually recognized that modulating inflammation is, therefore, an attractive avenue to forestall and treat atherosclerosis and its complications. Unfortunately, challenges with specificity and efficacy in managing plaque inflammation have hindered progress in atherosclerosis treatment. Herein, we report an NP-mediated mRNA therapeutic approach to target atherosclerotic lesional macrophages, modulating inflammation in advanced atherosclerotic lesions for the treatment of atherosclerosis. We demonstrated that the targeted NPs containing <i>IL-10</i> mRNA colocalized with M2-like macrophages and induced IL-10 production in atherosclerotic plaques following intravenous administration to Western diet (WD)-fed <i>Ldlr</i>^<i>-/-</i> mice. Additionally, the lesions showed a significantly alleviated inflammatory response, as evidenced by reduced oxidative stress and macrophage apoptosis, resulting in decreased lipid deposition, diminished necrotic areas, and increased fiber cap thickness. These results demonstrate the successful delivery of mRNA therapeutics to macrophage-enriched plaques in a preclinical model of advanced atherosclerosis, showing that this targeted NP inflammation management approach has great potential for translation into a wide range of clinical applications.