Mechano-programmed osteocyte-derived small extracellular vesicles for exercise-inspired osteoporosis therapy

Exercise is a potent physiological stimulus for maintaining skeletal homeostasis, but its transient mechanical cues cannot be directly delivered therapeutically. By revealing an exercise-responsive signaling axis involving osteocyte-derived small extracellular vesicles (sEVs), we developed a potential injectable, exercise-inspired nanovesicle strategy that converts defined mechanical stimulation into a transferable osteogenic miRNA signal. Mechanical programming of osteocytes with an optimized 8% cyclic strain for 12 h generated sEVs with enhanced osteogenic bioactivity. These mechano-programmed sEVs were internalized by bone marrow mesenchymal stem cells (BMSCs), where they promoted BMSC proliferation and osteogenic commitment. Following intravenous administration, DiR-labeled osteocyte-derived sEVs exhibited detectable long-bone-associated retention compared with free dye controls. In a hindlimb unloading-induced bone-loss model, systemically administered mechano-programmed sEVs restored trabecular bone microarchitecture and enhanced osteogenic activity, with BV/TV increasing from 5.32 ± 1.22% to 15.64 ± 1.68% and BMD increasing from 84.84 ± 7.04 (mg/cc) to 145.20 ± 13.10 (mg/cc). Mechanistically, mechanical programming encoded a three-miRNA signal—miR-2137, miR-149-3p, and miR-451a—into osteocyte-derived sEVs. This miRNA module convergently targeted OSR1, activated PI3K–AKT signaling, and thereby promoted BMSC osteogenic differentiation. Together, our findings establish mechano-programmed osteocyte-derived sEVs as a bone-origin vesicular strategy for translating exercise-associated mechanical cues into a potential injectable, exercise-inspired therapy for osteoporosis.