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.
Wang et al. (Sat,) studied this question.