Exercise-imitating adipocyte targeted poly-Lipidic DendroRNAi Nanovesicles for gene silencing-guided treatment of obesity in high-fat diet mouse model.

Abstract

Gene therapy is an emerging healthcare tool that balances the gene expression at molecular level. This study aims to develop adipocyte targeted anionic nanoformulation of RNAi for cytosolic delivery and RNase prevention. This investigation for the first time reports the development of cRGD labeled integrin targeted exercise mimicking RNAi nanoformulation for obesity treatment. Furthermore, this research investigate and validate ionizable lipid and dendrimer-driven micromachinery to mediate protonation-stimulated endosomal escape and cytosolic delivery of loaded miRNA therapeutics. To attain this goal, adipocyte-specific cRGD-labeled lipids have been synthesized to formulate integrin-targeted nanovesicles (NVs) of miR-130b for its safe and effective cytosolic delivery and to prevent its RNase degradation. The characterization or quality control of the developed NVs demonstrated uniform size distribution, anionic zeta potential, higher entrapment efficiency, cytosolic delivery aptitude, RNase protection aptitude, higher cellular uptake, and better safety profile. The efficacy of developed NVs in differentiated adipocytes altered various adipogenic markers. Furthermore, the in vivo pharmacodynamic efficacy by in vivo parameters demonstrated reduced animal weight, organ weight, improved exercise ability, better lipid profiling, downregulation of adipogenic and upregulation of lipolytic or metabolic mRNA and protein expression. The outcome of this research is expected to shed new lights towards research aimed at developing next-generational tool for treatment of obesity at molecular level.