Effects of Modified Messenger RNA of Adiponectin Delivered by Lipid Nanoparticles on Adipogenesis and Bone Metabolism In Vitro and In Vivo

TL;DR

This study shows that delivering modified adiponectin mRNA via lipid nanoparticles can reduce fat formation and promote bone healing in obese mice.

Contribution

The novel contribution is demonstrating the use of lipid nanoparticle-delivered APN mRNA to modulate adipogenesis and bone metabolism in vitro and in vivo.

Findings

APN-LNP inhibited adipogenesis in 3T3-L1 cells and enhanced osteogenic gene expression in MC3T3-E1 cells.

APN-LNP reduced matrix metalloproteinase 9 in RANKL-stimulated RAW264.7 cells, indicating anti-resorptive effects.

In vivo, APN-LNP promoted bone healing in diet-induced obese mice and reduced fasting blood glucose and body weight.

Abstract

Adiponectin (APN) is a secreted adipokine that plays a key role in modulating energy and bone metabolism, as well as regulating inflammatory responses. The overexpression of APN has been proposed as a potential therapeutic strategy for treating obesity and related disorders. Lipid nanoparticles (LNPs) are promising vectors for transporting messenger ribonucleic acid (mRNA) molecules. This study tested whether delivering a stabilized version of adiponectin mRNA (APN mRNA) using lipid nanoparticles could reduce fat formation and promote bone repair in vitro and in vivo. We demonstrated that transfection with APN-LNP upregulated the mRNA and protein expression of APN, while inhibiting adipogenesis in 3T3-L1 adipocytes. APN-LNP enhanced osteogenic gene expression in MC3T3-E1 cells in a dose-dependent manner. It also reduced matrix metalloproteinase 9 expression in receptor activator of nuclear factor-kappaB ligand (RANKL)-stimulated RAW264.7 cells, suggesting an anti-resorptive effect. In vivo, a femoral fracture model was established to explore the application of APN-LNP in promoting bone healing in diet-induced obese mice. Micro-computed tomography and histology analysis indicated that intravenous injection with APN-LNP promoted bone healing. Fasting blood glucose and body weight were decreased in the APN-LNP group. Moreover, APN-LNP increased bone sialoprotein and runt-related transcription factor 2 expression in contralateral femurs, as well as interleukin-10 expression in white adipose tissues. Thus, our study provides promising preclinical data on the potential use of APN-LNP for treating bone disorders in obesity.

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