Yuhe Jiang, Jianqi She, Zeying Wang, Yuan Zhu, Yunsong Liu, Ping Zhang, Hao Liu, Xiao Zhang, Yongsheng Zhou
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. 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. 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. ApoVs play a critical role in regulating bone-fat metabolism by orchestrating the balance between bone remodeling and lipid metabolism. This study revealed that while the fundamental properties of apoVs remained stable during development and aging, their functions and protein compositions were profoundly altered by donor aging. Thy1 was identified as a key biomarker, influencing apoV-mediated osteogenesis and adipogenesis. By engineering Thy1-enriched apoVs through magnetic-activated sorting and protein corona modification, we developed a highly effective therapeutic approach to restore senile bone-fat balance. Mechanistically, Thy1 enhanced osteogenic differentiation and suppressed adipogenesis in MSCs via activating the Thy1-ERK-TAZ axis. These findings systematically demonstrate the impact of donor aging on apoVs, paving the way for quality control and engineering of apoV-based strategy in aging-related metabolic diseases.