A MicroRNA and ROS‐Scavenger Co‐Loaded Nanogel for in Situ Macrophage Regulation and MR‐Visualized Treatment of Atherosclerosis

Atherosclerosis is a major pathophysiological factor in cardiovascular disease and is characterized by inflammatory responses and oxidative stress in plaques. Developing plaque microenvironment regulators for effective atherosclerosis treatment remains a great challenge owing to the pathological complexity, individual heterogeneity, and the limited efficiency of current medications. Herein, the integration of macrophage regulators and reactive oxygen species (ROS) scavengers into a nucleic acid nanogel platform is proposed for a highly efficient visualized treatment of atherosclerosis. As a proof-of-concept, an ROS scavenger with paramagnetic functionality, 2,2,6,6-tetramethylpiperidinyl-1-oxide (TEMPO), is selected for site-specific grafting onto single DNA strands via phosphorothioate groups to obtain TEMPO-DNA conjugates, which are subsequently assembled into TEMPO-grafted Y-shaped blocks with magnetic resonance imaging (MRI) capacity. Additionally, microRNA (miR-146a-5p) with macrophage-reprogramming ability is used as a crosslinker to integrate with the TEMPO-grafted blocks for preparing the multifunctional nanogel. With TEMPO inside, the nanoplatform enabled dynamic monitoring of disease progression and visualization of plaque treatment. The prepared drug co-delivery nanogels significantly relieved oxidative stress and regulated the inflammatory state of macrophages, leading to the remarkable regression and stabilization of plaques. Through its MRI capacity and synergistic therapeutic functionalities, this easy-to-prepare nanogel system provides a promising alternative strategy for imaging and visualizing the treatment of atherosclerotic plaques.