Multipathway Regulation for Targeted Atherosclerosis Therapy Using Anti-miR-33-Loaded DNA Origami.

Given the multifactorial pathogenesis of atherosclerosis (AS), a chronic inflammatory disease, combination therapy arises as a compelling approach to effectively address the complex interplay of pathogenic mechanisms for a more desired treatment outcome. Here, we present tDON, a nanoformulation based on a self-assembled DNA origami nanostructure for the targeted combination therapy of AS. tDON targets αβ integrin receptors overexpressed on pro-inflammatory macrophages and activated endothelial cells in atherosclerotic lesions, alleviates the oxidative stress induced by extracellular and endogenous reactive oxygen species, facilitates the polarization of pro-inflammatory macrophages toward the anti-inflammatory M2 phenotype, and inhibits foam cell formation by promoting cholesterol efflux from macrophages by downregulating miR-33. The antiatherosclerotic efficacy and safety profile of tDON, as well as its mechanism of action, were validated in an AS mouse model. tDON treatment reversed AS progression and restored normal morphology and tissue homeostasis of the diseased artery. Compared to probucol, a clinical antiatherosclerotic drug with a similar mechanism of action, tDON enabled the desired therapeutic outcome at a notably lower dosage. This study demonstrates the benefits of targeted combination therapy in AS management and the potential of self-assembled DNA nanoformulations in addressing multifactorial inflammatory conditions.