Engineering exosomes-mediated RNA delivery regulates bone homeostasis and alleviates osteoporosis

Osteoporosis is characterized by dysregulated bone remodeling driven by excessive osteoclast-mediated bone resorption and insufficient osteoblast-mediated bone formation, often exacerbated by chronic inflammation and oxidative stress. Current pharmacological therapies remain limited by suboptimal efficacy and adverse effects, highlighting the need for alternative strategies that restore bone homeostasis. Here, we developed a bone-targeted, multifunctional exosome-based therapeutic platform by engineering M2 macrophage-derived exosomes co-loaded with platinum nanoparticles (Pt NPs) and a miR-196b inhibitor (BT-Exo-Pt-miR-196 inhibitor). The engineered exosomes exhibited preserved structural integrity, favorable biocompatibility, efficient bone-targeting capability, and excellent in vivo biosafety. Pt NPs endowed the system with robust reactive oxygen species (ROS)-scavenging activity, while M2-derived exosomes and miR-196b inhibition synergistically attenuated inflammatory cytokine expression. In vitro, BT-Exo-Pt-miR-196 inhibitor markedly enhanced osteogenic differentiation, extracellular matrix maturation, and mineralization through coordinated upregulation of osteogenic transcription factors and matrix proteins. Concurrently, osteoclastogenesis was significantly suppressed, as evidenced by reduced TRAP-positive multinucleated cells, impaired actin ring formation, and downregulation of NFATc1 and downstream osteoclast-associated markers. In an ovariectomy-induced osteoporosis mouse model, bone-targeted delivery of BT-Exo-Pt-miR-196 inhibitor effectively preserved trabecular bone microarchitecture, enhanced osteogenic activity, reduced osteoclast function, and alleviated bone loss without inducing systemic toxicity. Collectively, this study demonstrates that bone-targeted M2 macrophage-derived exosomes delivering a miR-196b inhibitor represent a promising immunomodulatory and gene-regulatory nanotherapeutic strategy for restoring bone homeostasis and treating osteoporosis.