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.