Abstract

Skeletal aging involves pyrophosphate/phosphate disequilibrium and impaired mechanotransduction, which together constrain osteogenic repair. We develop OsteoVes, a matrix-vesicle-mimetic extracellular organelle that combines tissue-nonspecific alkaline phosphatase (ALP)-mediated inorganic pyrophosphate (PPi) hydrolysis, nano-hydroxyapatite nucleation, and a mesenchymal stem cell-derived membrane interface for extracellular matrix anchoring. In aged human mesenchymal stem/stromal cells (MSCs), OsteoVes restores the Pi/PPi set point, suppresses PPARG activity, promotes RUNX2 nuclear translocation, and supports osteogenic differentiation. OsteoVes also increases actomyosin tension and engages an ITG/FAK-PIEZO1-JNK/c-JUN-RUNX2 mechanotransduction-associated pathway. In elderly osteopenic/osteoporotic patient-derived MSCs, OsteoVes supports ALP activity and matrix mineralization. Systemic administration improves trabecular microarchitecture and mechanical properties in naturally aged mice within 4 weeks, remains active in Alpl +/− progeroid mice, and elicits osteoanabolic serum and imaging responses without evident short-term toxicity in metabolically aged rhesus macaques. These findings identify matrix vesicle (MV) dysfunction as an extracellular osteometabolic control point for short-term chemo-mechanical rescue.