Affiliation:
1. Department of Chemistry and Chemical Biology Rutgers The State University of New Jersey 123 Bevier Road Piscataway NJ 08854 USA
2. Chemical Biology Program Memorial Sloan Kettering Cancer Center New York NY 10065 USA
Abstract
AbstractExisting delivery methods for RNAi therapeutics encounter challenges, including stability, specificity, and off‐target effects, which restrict their clinical effectiveness. In this study, a novel miR‐133a zipper nanoparticle (NP) system that integrates miRNA zipper technology with rolling circle transcription (RCT) to achieve targeted delivery and specific regulation of miR‐133a in adipocytes, is presented. This innovative approach can greatly enhance the delivery and release of miR‐133a zippers, increasing the expression of thermogenic genes and mitochondrial biogenesis. he miR‐133a zipper NP is utilized for the delivery of miRNA zipper‐blocking miR‐133a, an endogenous inhibitor of Prdm16 expression, to enhance the thermogenic activity of adipocytes by modulating their transcriptional program. Inhibition of miR‐133a through the miR‐133a zipper NP leads to more significant upregulation of thermogenic gene expression (Prdm16 and Ucp1) than with the free miR‐133a zipper strand. Furthermore, miR‐133a zipper NPs increase the number of mitochondria and induce heat production, reducing the size of 3D adipose spheroids. In short, this study emphasizes the role of RNA NPs in improving RNAi stability and specificity and paves the way for broader applications in gene therapy. Moreover, this research represents a significant advancement in RNAi‐based treatments, pointing toward a promising direction for future therapeutic strategies.
Funder
National Heart, Lung, and Blood Institute
National Research Foundation of Korea
National Science Foundation Graduate Research Fellowship Program
Congressionally Directed Medical Research Programs
Alzheimer's Association
Foundation for the National Institutes of Health
New Jersey Commission on Spinal Cord Research
National Science Foundation