Delivery of m7G methylated Runx2 mRNA by bone-targeted lipid nanoparticle promotes osteoblastic bone formation in senile osteoporosis

The loss of bone and destruction of bone microstructure due to aging in senile osteoporosis (SOP) significantly impair the health and quality of life of the elderly. The pathogenesis of SOP is primarily related to osteogenic deficiency, attenuation of osteoblast function, insufficient bone formation, and eventual bone loss. While METTL1 is the major reported methyltransferase to catalyze RNA 7-methylguanosine (m7G) methylation, regulating mRNA transcription, miRNA biosynthesis, biological function, tRNA stability, RNA intracellular processing, and maturation, its role in the pathogenesis of SOP and osteogenic differentiation of BMSCs has not been studied. In this research, we found a significant decrease in METTL1 in BMSCs from SOP patients. Deletion of METTL1 significantly inhibited m7G modification of Runx2, impeding osteogenic differentiation of BMSCs in vitro and inducing SOP in vivo. We further developed bone-targeted lipid nanoparticles containing the m7G methylated Runx2 mRNA (ZA-m7G Runx2 mRNA-LNPs), which significantly promoted bone repair and formation in the bone defect mouse model as well as the SOP mouse. This study provides new basic theoretical theory and treatment strategies for the prevention and treatment of SOP by revealing a critical m7G RNA modification mechanism of osteogenic differentiation disorders of BMSCs in the pathogenesis of SOP.