Abstract：
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.
摘要：
鉴于动脉粥样硬化（AS）的多因素发病机制，慢性炎症性疾病,联合治疗是一种令人信服的方法，可以有效解决致病机制之间复杂的相互作用，从而获得更理想的治疗结果。这里,我们介绍cRGD/ASOtDON，一种基于自组装DNA折纸纳米结构的纳米制剂，用于AS的靶向联合治疗。cRGD/ASOtDON靶向动脉粥样硬化病变中促炎症巨噬细胞和活化内皮细胞过度表达的αvβ3整合素受体，减轻细胞外和内源性活性氧引起的氧化应激，促进促炎巨噬细胞向抗炎M2表型的极化，并通过下调miR-33促进巨噬细胞的胆固醇流出来抑制泡沫细胞形成。cRGD/ASOtDON的抗动脉粥样硬化疗效和安全性，以及它的作用机制，在AS小鼠模型中进行了验证。cRGD/ASOtDON治疗逆转了AS进展并恢复了病变动脉的正常形态和组织稳态。与普罗布考相比,具有相似作用机制的临床抗动脉粥样硬化药物，cRGD/ASOtDON以明显较低的剂量实现了所需的治疗结果。这项研究证明了靶向联合治疗在AS管理中的益处以及自组装DNA纳米制剂在解决多因素炎性病症中的潜力。
