Targeting Endogenous Lipophagy: A Novel Strategy to Enhance MSC Osteogenesis and Mineralization for Senile Osteoporosis Therapy.

Senile osteoporosis (SOP) is characterized by impaired osteogenesis of bone-marrow mesenchymal stem cells (MSCs). The underlying metabolic basis remains unclear. This study aimed to identify energy-regulating pathways sustaining MSC osteogenesis during aging. Progressive activation of lipophagy was observed during MSC osteogenic differentiation, coupling lipid-droplet degradation with mitochondrial β-oxidation and ATP generation. Loss of the lipophagy receptor SPARTIN disrupted this process, leading to lipid accumulation, reduced CPT1A/CPT2 expression, suppressed oxidative phosphorylation, and impaired osteogenesis in vitro and in vivo. Conditional deletion of Spart in MSCs reproduced an osteoporosis-like phenotype in young mice. Reactivation of lipophagy using bone-tropic AAV9-LAP restored mitochondrial metabolism and bone mass in both Spart-CKO and SOP mice. Pharmacological activation with digoxin produced similar effects but induced cardiotoxicity. A senescent-neutrophil-membrane-coated nanoplatform (SNM@NP-DIG) enabled bone-targeted digoxin delivery, rescuing bone mass while minimizing cardiac injury. Overall, SPARTIN-mediated lipophagy is a critical metabolic regulator of MSC osteogenesis and represents a promising therapeutic target for senile osteoporosis.