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

ABSTRACT 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.