Inflammatory Macrophage-Targeted Atherosclerosis Treatment by miRNA-Delivered, MRI-Visible, and Anti-Inflammatory Nanomedicine

Abstract

Atherosclerosis, a principal cause of fatal cardiovascular diseases, is fundamentally a chronic inflammatory disease. Addressing this, the combined regulation of oxidative stress and inflammation through synergistic modalities offers an efficient therapeutic avenue. In this work, we rationally designed and engineered a highly efficient functional nanosystem, referred to as polydopamine nanoparticles doped with arginine and gadolinium ions (AGPDAR-146a), for the targeted delivery of therapeutic oligonucleotides, specifically microRNA-146a (miR-146a), to inflammatory macrophages within atherosclerotic plaques. AGPDAR-146a nanoparticles effectively load and deliver miR-146a, achieving enhanced accumulation in inflammatory macrophages through the specific interaction between miR-146a and class A scavenger receptors. Functionally, AGPDAR-146a nanoparticles excel in eliminating reactive oxygen species and exert anti-inflammatory effects, principally by modulating the nuclear factor kappa-light-chain-enhancer of activated B cells pathway and the interferon regulatory factor 5 protein, consequently helping to reduce and stabilize atherosclerotic plaques. Additionally, the intrinsic T₁ magnetic resonance imaging capability of AGPDAR-146a nanoparticles enables real-time visualization of the progression of plaque inflammation. Therefore, the engineered nanosystem not only underscores the therapeutic potential of miR-146a in atherosclerosis but also illustrates a versatile microRNA delivery strategy applicable to various diseases characterized by oxidative stress and inflammation.