Bone‐Homing Cellular Backpacks Integrating Metabolic Intervention and Synergistic Osteogenesis to Treat Bone Metastasis and Promote Diabetic Bone Repair

ABSTRACT Dysregulated osteoclast activity underlies pathological bone resorption in skeletal metastases and metabolic bone disorders such as diabetes, yet effective therapeutic strategies remain scarce. Here, we present a mesenchymal stem cell (MSC)‐based cellular backpack platform for metabolism‐guided and bone‐targeted therapy. This biohybrid system couples MSCs with lipid‐coated, biotin‐streptavidin‐linked nanoparticles that encapsulate the phosphoglycerate dehydrogenase (PHGDH) inhibitor NCT503 and are enriched with calcium via biomineralization. Driven by CXCR4‐mediated MSC homing, the cellular backpacks selectively localize to osteoclast‐ and tumor‐rich bone microenvironments. NCT503 inhibits the serine synthesis pathway, suppressing NFATc1‐dependent osteoclastogenesis and tumor progression, while calcium ions disrupt the reciprocal metabolic coupling between osteoclasts and cancer cells. Simultaneously, calcium enrichment enhances MSC chemotaxis, migration, and osteogenic differentiation, enabling precise delivery and bone regeneration. In murine models of bone metastasis and diabetic fracture, this strategy mitigates osteolysis, restrains tumor growth, and accelerates skeletal repair. Collectively, this study introduces a multifunctional, cell‐guided therapeutic platform that synergistically integrates metabolic intervention, osteoclast‐tumor modulation, and regenerative repair, offering a promising avenue for the treatment of dysregulated bone diseases.