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

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/ASO tDON, a nanoformulation based on a self-assembled DNA origami nanostructure for the targeted combination therapy of AS. cRGD/ASO tDON targets α v β 3 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/ASO tDON, as well as its mechanism of action, were validated in an AS mouse model. cRGD/ASO 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, cRGD/ASO 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.

DNA Origami Enhanced Cytokine Immunotherapy for Alleviating Renal Ischemia-Reperfusion Injury

“…DNA origami has emerged as a promising nanocarrier for targeted disease treatment, efficiently enhancing the therapeutic outcomes of various drugs. − In particular, its ability to exhibit preferential renal uptake renders DNA origami a promising delivery platform for the treatment of renal diseases. ,, Flat DNA origami, such as rectangular DNA origami, can precisely manipulate biomolecules on their surface due to their sub-10 nm addressability. − Thus, many proteins, including IL-10, can be effectively loaded onto the DNA origami surface. Furthermore, DNA origami exhibits remarkable sensitivity to various ROS, positioning it as a potential scavenger for effectively eliminating ROS. ,, In addition to its excellent biocompatibility, biodegradability, and low immunogenicity, − DNA origami can serve as a functional and renal-targeting delivery platform.…”