A bone-targeted engineered exosome platform delivering siRNA to treat osteoporosis

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-si<i>Shn3</i>, took advantage of the intrinsic anti-osteoporosis function of these special MSC-derived exosomes and collaborated with the loaded siRNA of the <i>Shn3</i> gene to enhance the therapeutic effects. Modification of a bone-targeting peptide endowed the BT-Exo-si<i>Shn3</i> an ability to deliver siRNA to osteoblasts specifically. Silencing of the osteoblastic <i>Shn3</i> gene enhanced osteogenic differentiation, decreased autologous RANKL expression and thereby inhibited osteoclast formation. Furthermore, <i>Shn3</i> gene silencing increased production of SLIT3 and consequently facilitated vascularization, especially formation of type H vessels. Our study demonstrated that BT-Exo-si<i>Shn3</i> could serve as a promising therapy to kill three birds with one stone and implement comprehensive anti-osteoporosis effects.