Related Experiment Video
Updated: Jul 4, 2025
Delivery of Modified mRNA in a Myocardial Infarction Mouse Model
Published on: June 11, 2020
Multipathway Regulation for Targeted Atherosclerosis Therapy Using Anti-miR-33-Loaded DNA Origami
Yuxuan Ma1,2, Qi Wang1,2, Shiyu Du1,2
1Department of Biomedical Engineering, College of Engineering and Applied Sciences, Nanjing University, Nanjing, Jiangsu 210023, P. R. China.
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.
Insights
A novel DNA nanostructure, cRGD/ASO tDON, offers targeted combination therapy for atherosclerosis by reducing inflammation and foam cell formation. This approach shows significant potential for managing this chronic inflammatory disease.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cardiovascular Research
Background:
- Atherosclerosis (AS) is a chronic inflammatory disease with complex, multifactorial pathogenesis.
- Combination therapy is a promising strategy to address the intricate mechanisms of AS.
- Targeted delivery systems can enhance therapeutic efficacy and minimize side effects.
Purpose of the Study:
- To develop and evaluate a novel DNA origami nanostructure, cRGD/ASO tDON, for targeted combination therapy of atherosclerosis.
- To investigate the mechanism of action of cRGD/ASO tDON in modulating inflammatory responses and lipid metabolism in AS.
- To assess the antiatherosclerotic efficacy and safety of cRGD/ASO tDON in a preclinical model.
Main Methods:
- Fabrication of a self-assembled DNA origami nanostructure (cRGD/ASO tDON).
- Targeting of αvβ3 integrin receptors overexpressed on macrophages and endothelial cells in atherosclerotic lesions.
- Evaluation of effects on oxidative stress, macrophage polarization, and foam cell formation (miR-33 downregulation).
- In vivo validation in an atherosclerosis mouse model, comparing efficacy to probucol.
Main Results:
- cRGD/ASO tDON effectively targeted atherosclerotic lesions.
- The nanostructure alleviated oxidative stress, promoted M2 macrophage polarization, and inhibited foam cell formation.
- In vivo studies demonstrated reversal of AS progression and restoration of arterial homeostasis.
- cRGD/ASO tDON achieved therapeutic outcomes at a lower dosage compared to probucol.
Conclusions:
- Targeted combination therapy using self-assembled DNA nanoformulations is a viable strategy for managing atherosclerosis.
- cRGD/ASO tDON demonstrates significant antiatherosclerotic efficacy and a favorable safety profile.
- This study highlights the potential of DNA nanostructures in addressing multifactorial inflammatory diseases.
Related Concept Videos
02:15Experimental RNAi
01:22MicroRNAs