The complex pathogenesis of osteoporosis includes excessive bone resorption, insufficient bone formation and inadequate vascularization, a combination which is difficult to completely address with conventional therapies. Engineered exosomes carrying curative molecules show promise as alternative osteoporosis therapies, but depend on specifically-functionalized vesicles and appropriate engineering strategies. Here, we developed an exosome delivery system based on exosomes secreted by mesenchymal stem cells (MSCs) derived from human induced pluripotent stem cells (iPSCs). The engineered exosomes BT-Exo-siShn3, took advantage of the intrinsic anti-osteoporosis function of these special MSC-derived exosomes and collaborated with the loaded siRNA of the Shn3 gene to enhance the therapeutic effects. Modification of a bone-targeting peptide endowed the BT-Exo-siShn3 an ability to deliver siRNA to osteoblasts specifically. Silencing of the osteoblastic Shn3 gene enhanced osteogenic differentiation, decreased autologous RANKL expression and thereby inhibited osteoclast formation. Furthermore, Shn3 gene silencing increased production of SLIT3 and consequently facilitated vascularization, especially formation of type H vessels. Our study demonstrated that BT-Exo-siShn3 could serve as a promising therapy to kill three birds with one stone and implement comprehensive anti-osteoporosis effects.

骨质疏松症的发病机制复杂，包括过度的骨吸收、骨形成不足和血管化不足，这是传统疗法难以完全解决的组合问题。携带治疗性分子的工程外泌体显示出作为替代骨质疏松症疗法的前景，但取决于特定功能化的囊泡和适当的工程策略。在这里，我们开发了一种基于源自人类诱导多能干细胞 (iPSC) 的间充质干细胞 (MSC) 分泌的外泌体的外泌体递送系统。工程外泌体BT-Exo-si Shn3，利用这些特殊的MSC衍生的外泌体固有的抗骨质疏松功能，并与Shn3的负载siRNA协作基因来增强治疗效果。骨靶向肽的修饰赋予 BT-Exo-si Shn3将 siRNA 特异性递送至成骨细胞的能力。成骨细胞Shn3基因的沉默增强了成骨分化，降低了自体 RANKL 表达，从而抑制了破骨细胞的形成。此外，Shn3基因沉默增加了 SLIT3 的产生，从而促进了血管形成，尤其是 H 型血管的形成。我们的研究表明，BT-Exo-si Shn3可以作为一种很有前景的疗法，一石三鸟，并实现全面的抗骨质疏松症效果。