Intercellular Communication‐Driven Mitochondrial Transfer via CXCR4‐Engineered Macrophages Reprograms Bone Marrow Metabolism for Osteoporosis Therapy

Abstract

ABSTRACT Osteoporosis is characterized by impaired bone formation and disrupted bone marrow homeostasis, largely driven by mitochondrial dysfunction in bone marrow mesenchymal stem cells (BMSCs). To address this, a live mitochondrial delivery system composed of CXCR4‐engineered macrophages loaded with nanozyme‐functionalized mitochondria (CM‐MTBM). This system integrates bone‐targeted migration, reactive oxygen species scavenging, and communication‐mediated mitochondrial transfer. CM‐MTBM restores mitochondrial respiration, enhances osteogenic differentiation, and alleviates oxidative apoptosis in BMSCs, thereby promoting metabolic recovery and redox balance. In osteoporotic mice, CM‐MTBM treatment markedly improved the trabecular bone microarchitecture and promoted osteogenic repair. Single‐cell transcriptomic analysis further revealed the enrichment of osteogenic BMSC subpopulations and functional reprogramming of the bone marrow immune–metabolic microenvironment. Mechanistically, CM‐MTBM activated mitochondrial oxidative metabolism while suppressing inflammation and senescence‐associated signaling, achieving coordinated metabolic and osteogenic activation. Collectively, this work established a communication‐driven mitochondrial transfer paradigm that reframes mitochondrial therapy from passive structural supplementation to communication‐driven metabolic reprogramming, establishing a conceptual and technological framework for precision treatment of metabolic bone disorders.