Abstract

Inflammatory events triggered by lipoproteins trapped in the intima of arteries promote the development of atherosclerosis (AS). Therefore, modulating inflammation is considered to be an efficient therapeutic avenue. Atherosclerotic plaques are characterized by defective autophagy, which aggravates inflammation and predisposes cells to apoptosis and necrosis. Meanwhile, necrotic cells release cell-free DNA (cfDNA), which activates DNA sensors and further amplifies the inflammatory cascade. Accordingly, the combined therapy of inducing autophagy and scavenging cfDNA is expected to alleviate the inflammatory response in AS. Herein, we fabricated a nanodrug delivery system (NDDS), R@PS45, which targeted atherosclerotic plaques and released the autophagy inducer rapamycin (Rapa) and cfDNA scavenger d-PSn in response to elevated reactive oxygen species (ROS) and the weakly acidic plaque microenvironment. Rapa repaired autophagy defects of plaques to alleviate AS development, while d-PSn in response to elevated reactive oxygen species (ROS) and the weakly acidic plaque microenvironment. Rapa repaired autophagy defects of plaques to alleviate AS development, while d-PSn scavenged cfDNA from inflamed dying cells to inhibite DNA sensors activation, thus synergistically suppressing inflammatory progression. Notably, R@PS45 could enter cells via membrane permeabilization to capture cfDNA and transport it to lysosomes for degradation through induced autophagy. In the ApoE–/– mouse model, R@PS45 exerted antiatherosclerotic efficacy by markedly reducing aortic plaque burden, decreasing serum cfDNA and proinflammatory cytokine levels, and enhancing plaque stability. Collectively, this study establishes a promising multifunctional nanoplatform for the synergistic treatment of AS and provides an available strategy for the development of therapeutics against inflammation-driven diseases.