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.

中文翻译：

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用于骨质疏松症治疗的表达核因子 κ-B 的间充质干细胞来源的细胞外囊泡的受体激活剂


骨吸收和形成之间的动态平衡对于维持健康的骨稳态至关重要。然而，核因子 B 配体 （RANKL） 的受体激活剂主要刺激成熟的破骨细胞重新吸收骨骼，其上调导致患者骨质疏松症。在这里，我们设计了源自间充质干细胞的表达 RANK 的细胞外囊泡 （EV） 来维持小鼠的骨稳态。由于 RANK-RANKL 相互作用，这种工程化 EV （EV@R） 可有效中和骨组织中过量的 RANKL，从而减弱破骨细胞分化。此外，我们发现 EV@R 中的 miRNA-21a-5p 有助于恢复骨代谢稳态。我们在卵巢切除术诱导的骨质疏松症小鼠模型中证明了 EV@R 对骨质疏松症的保护和治疗作用，具有持久的效果和最小的副作用。我们的研究提供了一种使用工程化 EV 进行骨稳态治疗的替代方法。