Receptor Activator\nof Nuclear Factor Kappa-B-Expressing\nMesenchymal Stem Cells-Derived Extracellular Vesicles for Osteoporosis\nTherapy

The dynamic balance between bone resorption and formation\nis critical\nfor maintaining healthy bone homeostasis. However, the receptor activator\nof the nuclear factor B ligand (RANKL) primarily stimulates mature\nosteoclasts to resorb bone, and its upregulation leads to osteoporosis\nin patients. Here, we designed RANK-expressing extracellular vesicles\n(EVs) derived from mesenchymal stem cells to maintain bone homeostasis\nin mice. This engineered EV (EV@R) effectively neutralizes excess\nRANKL in bone tissue due to the RANK–RANKL interaction, thereby\nattenuating osteoclast differentiation. Additionally, we found that\nmiRNA-21a-5p in EV@R contributes to restoring bone metabolic homeostasis.\nWe demonstrate the protective and therapeutic efficacy of EV@R against\nosteoporosis in the ovariectomy-induced osteoporosis mouse model with\na lasting effect and minimal side effects. Our study provides an alternative\nway to use engineered EVs for bone homeostasis treatment.