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. Compared to model, a three-month regimen of RT-rHDL nanoassemblies in apoE-/- mice resulted in marked reductions on plaque size by 40.38%, necrotic core area by 35.41%, and lipid droplet content by 55.5%, alongside a resolution of local inflammation as evidenced by diminished macrophage infiltration (84.36%), monocyte recruitment (76.2%) and MMP-9 secretion (67.4%). Also, RT-rHDL nanoassemblies treatment enhanced plaque stability as indicated by increased collagen content (66.38%) and α-SMA expression (143.06%). 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.