Milk-derived exosome-based strategy targeting ferroptosis-glycolysis network promotes bone regeneration in diabetic aging comorbidity.

Diabetes and aging synergistically impair bone regeneration, primarily driven by functional deterioration of bone marrow mesenchymal stem cells (BMSCs). Here, we uncover an m6A-centered regulatory network integrating ferroptosis and glycolytic metabolism that dictates BMSCs dysfunction under diabetes-aging comorbidity. Mechanistically, diabetic stress selectively activated the ALKBH5-ferroptosis axis, driving excessive ferroptosis in young BMSCs, whereas senescent BMSCs exhibited an additional repression of METTL3-mediated glycolytic flux, rendering ferroptosis inhibition alone insufficient to restore osteogenic capacity. These intersecting molecular defects cooperatively exacerbated osteoporosis progression in diabetic aging. Guided by this mechanistic framework, we developed a combinatorial regenerative strategy integrating milk-derived exosomes (MiExos) and anaerobic exercise to simultaneously target ferroptotic stress and metabolic insufficiency. Mechanistically, MiExos selectively suppressed ferroptosis by stabilizing NRF2 signaling through inhibition of ubiquitination, without perturbing glycolytic metabolism, while anaerobic exercise robustly enhanced intraosseous glycolysis. Notably, the dual intervention markedly improved bone regeneration in diabetic-aged mice. Collectively, our findings establish milk-derived exosomes as a natural nanotherapeutic capable of precise ferroptosis modulation and demonstrate that coordinated suppression of ferroptosis and activation of glycolysis is essential for overcoming bone regenerative failure in diabetes-aging comorbidity.