Developing MiR‐133a Zipper Nanoparticles for Targeted Enhancement of Thermogenic Adipocyte Generation

Abstract

Existing delivery methods for RNAi therapeutics encounter challenges, including stability, specificity, and off‐target effects, which restrict their clinical effectiveness. In this study, we present a novel miR‐133a zipper nanoparticle system that integrates miRNA zipper technology with rolling circle transcription to achieve targeted delivery and specific regulation of miR‐133a in adipocytes. This innovative approach could greatly enhance the delivery and release of miR‐133a zippers, increasing the expression of thermogenic genes and mitochondrial biogenesis. To show the therapeutic potential of this design, the miR‐133a zipper nanoparticle was 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 our miR‐133a zipper nanoparticle led to more significant upregulation of thermogenic gene expression (Prdm16 and Ucp1) than with the free miR‐133a zipper strand. Furthermore, miR‐133a zipper nanoparticles increased the amount of mitochondria and induced heat production, reducing the size of 3D adipose spheroids. In short, our study emphasizes the role of RNA nanoparticles 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 towards a promising direction for future therapeutic strategies.This article is protected by copyright. All rights reserved