Young plasma-derived exosomes deliver YOD1 to induce M2 polarization and ameliorate osteoporosis via mTOR signaling pathways.

This study aimed to evaluate the therapeutic potential of young plasma-derived exosomes (Y-Exos) in osteoporosis, focusing on their capacity to modulate macrophage polarization and bone homeostasis. Ovariectomized (OVX) mice were administered young plasma, aged plasma, exosome-depleted plasma, or plasma-derived exosomes. Bone mass, macrophage polarization, and osteoblast/osteoclast activity were analyzed by micro-CT, flow cytometry, and histology. Human Y-Exos were isolated to examine their direct effects on BMSC osteogenesis and BMM polarization, as well as indirect effects on osteoclastogenesis. Proteomic and transcriptomic approaches were employed to identify key functional proteins and underlying mechanisms. For results, young plasma significantly improved bone mass, increased CD206+M2 macrophages, and upregulated osteogenic and anti-inflammatory genes in OVX mice-effects that were largely abolished upon exosome depletion. Y-Exos were internalized by target cells, promoted BMSC osteogenesis, reduced M1 markers (CD86, iNOS) in LPS-stimulated BMMs, and enhanced M2 markers (CD206, ARG1), and, indirectly, reversed osteoclast activation and rescued osteogenic suppression. In vivo, Y-Exos increased bone mass, elevated OCN and CD206 expression, and expanded the Lin-Sca-1+c-Kit+ (LSK) cell population. YOD1 was identified as a key effector in Y-Exos and was downregulated with aging. Mechanistically, Y-Exos delivered YOD1 to activate mTOR in BMMs, driving M2 polarization, and to BMSCs, promoting osteogenesis via Hippo signaling. In conclusion, Y-Exos deliver YOD1 to induce M2 macrophage polarization through mTOR activation and enhance osteogenesis via Hippo signaling, thereby improving the bone immune microenvironment and effectively ameliorating osteoporosis. These findings reveal a new immunomodulatory mechanism and provide an experimental basis for Y-Exos-based therapy in osteoporosis.