Harnessing GMNP-loaded BMSC-derived EVs to target miR-3064-5p via MEG3 overexpression: Implications for diabetic osteoporosis therapy in rats

Diabetic osteoporosis (DO) is a significant complication of diabetes, characterized by a decrease in bone mineral density and an increase in fracture risk. Magnetic nanoparticles (GMNPs) have emerged as potential drug carriers for various therapeutic applications. This study investigated the molecular mechanism of GMNPs loaded with bone marrow mesenchymal stem cell (BMSC) derived extracellular vesicles (EVs) overexpressing MEG3 target miR-3064-5p to induce NR4A3 for treating DO in rats. Initial analysis was carried out on GEO datasets GSE7158 and GSE62589, revealing a notable downregulation of NR4A3 in osteoporotic samples. Subsequent in vitro studies demonstrated the effective uptake of BMSC-EVs-MEG3 by osteoblasts and its potential to inhibit miR-3064-5p, activating the PINK1/Parkin signaling pathway and thus promoting mitochondrial autophagy, osteoblast proliferation, and differentiation. In vivo, experiments using DO rat models further substantiated the therapeutic efficacy of GMNPE-EVs-MEG3 in alleviating osteoporosis symptoms. In conclusion, GMNPs loaded with BMSC-EVs, through the delivery of MEG3 targeting miR-3064-5p, can effectively promote NR4A3 expression, activate the PINK1/Parkin pathway, and thereby enhance osteoblast proliferation and differentiation, offering a promising treatment for DO.