Apoptotic vesicles rectify senile bone-fat imbalance by activating Thy1-ERK-TAZ axis.

BACKGROUND: Senile bone-fat imbalance poses a significant public health burden in aging populations. This study investigates how aging affects the heterogeneity of mesenchymal stem cell (MSC)-derived apoptotic vesicles (apoVs) and develops a therapeutic strategy to rectify age-related bone-fat metabolic disorders. RESULTS: Protein cargo analysis revealed that MSC-derived apoVs undergo age-dependent compositional remodeling, with Thy1 identified as a key biomarker progressively declining with donor aging. Functional validation confirmed Thy1's critical role in mediating apoV osteoinductive and anti-adipogenic capacities. Engineered Thy1-enriched apoVs, produced through magnetic-activated sorting and protein corona technology, significantly enhanced osteogenesis and suppressed adipogenesis in recipient MSCs by activating the Thy1-ERK-TAZ signaling axis. In aged mouse models, these engineered apoVs restored trabecular bone mass, reduced marrow adipose tissue, and ameliorated systemic lipid metabolism disorders. CONCLUSIONS: This work establishes Thy1 as a functional biomarker for aging-related apoV heterogeneity and demonstrates that engineered Thy1-enriched apoVs represent a clinically scalable therapeutic approach for senile bone-fat imbalance. The identified Thy1-ERK-TAZ mechanism provides a tunable platform for developing extracellular vesicle-based interventions against age-related metabolic diseases.