Receptor Activator of Nuclear Factor Kappa-B-Expressing Mesenchymal Stem Cells-Derived Extracellular Vesicles for Osteoporosis Therapy
Wenju Chang, Bo Tian, Qin Qin, Dongxiao Li, Yue Zhang, Chenmeng Zhou, Bingbing Wu, Mingchao Zhang, Huajian Shan, Yichao Ni, Qirong Dong, Chao Wang, Xiaozhong Zhou, Jinyu Bai
Abstract
The dynamic balance between bone resorption and formation is critical for maintaining healthy bone homeostasis. However, the receptor activator of the nuclear factor B ligand (RANKL) primarily stimulates mature osteoclasts to resorb bone, and its upregulation leads to osteoporosis in patients. Here, we designed RANK-expressing extracellular vesicles (EVs) derived from mesenchymal stem cells to maintain bone homeostasis in mice. This engineered EV (EV@R) effectively neutralizes excess RANKL in bone tissue due to the RANK-RANKL interaction, thereby attenuating osteoclast differentiation. Additionally, we found that miRNA-21a-5p in EV@R contributes to restoring bone metabolic homeostasis. We demonstrate the protective and therapeutic efficacy of EV@R against osteoporosis in the ovariectomy-induced osteoporosis mouse model with a lasting effect and minimal side effects. Our study provides an alternative way to use engineered EVs for bone homeostasis treatment.