%0 Journal Article
%T Multipathway Regulation for Targeted Atherosclerosis Therapy Using Anti-miR-33-Loaded DNA Origami.
%A Ma Y
%A Wang Q
%A Du S
%A Luo J
%A Sun X
%A Jia B
%A Ge J
%A Dong J
%A Jiang S
%A Li Z
%J ACS Nano
%V 0
%N 0
%D 2024 Feb 6
%M 38321605
%F 18.027
%R 10.1021/acsnano.3c10213
%X 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 cRGD/ASOtDON, a nanoformulation based on a self-assembled DNA origami nanostructure for the targeted combination therapy of AS. cRGD/ASOtDON targets αvβ3 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 cRGD/ASOtDON, as well as its mechanism of action, were validated in an AS mouse model. cRGD/ASOtDON 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, cRGD/ASOtDON 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.