Site‐Specific MicroRNA‐33 Antagonism by pH‐Responsive Nanotherapies for Treatment of Atherosclerosis via Regulating Cholesterol Efflux and Adaptive Immunity

Abstract

Atherosclerosis remains the leading cause of a broad spectrum of deadliest cardiovascular diseases. MicroRNA-33 is a new therapeutic target for atherosclerosis due to its diverse functions. However, it remains a great challenge in clinical translation of nucleic acid-based microRNA-targeting therapeutics. Considering lesional acidosis, herein cyclodextrin-derived pH-responsive and integrin-targeting nanoparticles containing an antisense oligonucleotide against microRNA-33 (anti-miR33) are engineered for precision therapy of atherosclerosis. A desirable anti-miR33 nanotherapy (AAM NP) is initially developed by screening carrier materials. AAM NP is further decorated with a peptide ligand cRGDfK for integrin to afford an active targeting nanotherapy RAAM NP, to achieve more effective delivery of anti-miR33 to plaques and target cells. Both nanotherapies can be efficiently internalized by different cells relevant to atherosclerosis. After intravenous delivery, AAM NP passively accumulates in atherosclerotic plaques and related cells in apolipoprotein E-deficient mice. Correspondingly, AAM NP treatment significantly attenuates atherosclerosis in mice and notably reduces vulnerable plaques. Decoration with cRGDfK considerably enhances the targeting capability and therapeutic effects of RAAM NP. Mechanistically, anti-miR33 nanotherapies significantly promote reverse cholesterol transport and notably regulate adaptive immunity via modulating macrophage polarization and regulatory T cell differentiation. Consequently, the pH-responsive anti-miR33 nanotherapies are promising for targeted treatment of atherosclerosis.

Nanoparticle-Based Approaches towards the Treatment of Atherosclerosis

“…Since several classes of nanoparticles are used to design nanoformulated therapeutics, in this section we briefly overview the most common synthesis procedures of organic (liposomal, polymer-based, and solid lipid) and inorganic (metal and metal oxide) nanoparticles. In addition to the synthetic approaches listed and described below, additional particle modifications could be introduced including: core-shell structures formation [41], electrostatic [42], and covalent [43] surface modification, self-assembled suprastructures formation [44][45][46][47][48]. A large number of micro-and nano-sized systems for biomedical applications including atherosclerosis treatment could be produced by following these procedures.…”

“…miR-33 causes a lot of atherosclerosis manifestations because it is responsible for lipid metabolism, fatty acid oxidation, and autophagy of macrophages [136]. However, some additional positive changes were observed in mice treated with NPs loaded with miR-33 [48]. It is crucial to mention, that the authors managed to achieve both a high loading rate of 88% and a complete release of miR-33 (>96%).…”

“…The researchers have managed to achieve a high loading rate (65.4 ± 5.8% from the initial drug input weight) and almost complete release (84.4% over 8 days). A similar case based on the prevention of cholesterol efflux in macrophages was achieved by silencing miR-33 micro-RNA (Table 2) [48]. miR-33 causes a lot of atherosclerosis manifestations because it is responsible for lipid metabolism, fatty acid oxidation, and autophagy of macrophages [136].…”

“…Nanoprecipitation is based on rapid micromixing which creates high supersaturation conditions leading to the precipitation and encapsulation of hydrophobic drugs in a polymer-based delivery vehicle [56]. The flash nanoprecipitation was extensively used for nanocarrier for atherosclerosis therapy design [44,48,57]. Wang et al designed the carrier via covalent conjugation of a superoxide dismutase mimetic agent Tempol and a hydrogen peroxide-eliminating compound of phenylboronic acid pinacol ester onto a cyclic polysaccharide β-cyclodextrin (Table 1) [57].…”

“…Lewis et al created the sugar-based amphiphilic macromolecules to competitively block oxidized lipid uptake via scavenger receptors on macrophages [44]. Dou with co-authors used a facile synthesis of biocompatible materials from αor β-cyclodextrin and their polymers to load and deliver anti-miR33 into target cells [48].…”