Engineering ROS-responsive size-transformable nanoassemblies to reprogram plaque microenvironment and activate autophagy for atherosclerosis therapy

Oxidative stress and macrophage autophagy dysfunction jointly drive plaque vulnerability and rupture, ultimately leading to acute atherothrombotic cardiovascular events. However, current monotherapies based solely on antioxidant intervention or autophagy induction remain insufficient for effective atherosclerosis management. Here, we reported the development of a cationic antioxidant dextran derivative (DKT) with intrinsic reactive oxygen species (ROS)-scavenging capacity, designed to co-deliver rapamycin-loaded reconstituted high-density lipoprotein (RC-rHDL) for synergistic atherosclerosis therapy. Through electrostatic interactions, DKT mediated the assembly of small-sized RC-rHDL into large-sized nanoassemblies (RT-rHDL), enabling efficient vascular targeting and ROS-triggered disassembly within plaques. In vitro studies demonstrated that RT-rHDL nanoassemblies effectively inhibited foam cell formation, suppressed inflammation, and reduced apoptosis by combining ROS elimination with autophagy activation. In vivo, RT-rHDL nanoassemblies accumulated at atherosclerotic lesions via endothelial binding and penetrated deeply into foam cell–rich plaques. A three-month intravenous treatment in apoE −/− mice significantly reduced plaque size, minimized necrotic core areas, resolved local inflammation, and enhanced plaque stability. Mechanistic investigations confirmed that systemic and lesional oxidative stress attenuation together with macrophage autophagy restoration underpinned these therapeutic benefits. Collectively, our findings highlight the importance of simultaneously modulating cellular functions and the plaque microenvironment, offering a novel synergistic nanotherapeutic strategy for atherosclerosis treatment.