Orchestration of energy metabolism and osteogenesis by Mg2+ facilitates low-dose BMP-2-driven regeneration

The clinical application of bone morphogenetic protein-2 (BMP-2) is limited by several factors, including ineffectiveness at low doses and severe adverse effects at high doses. To address these efficacy and safety limitations, we explored whether orchestration of energy metabolism and osteogenesis by magnesium ion (Mg2+) could reduce the dose and thereby improve the safety of BMP-2. Our results demonstrated that rapid metabolic activation triggered by BMP-2 was indispensable for subsequent osteogenesis. Moreover, inadequate metabolic stimulation was shown to be responsible for the ineffectiveness of low-dose BMP-2. Next, we identified that Mg2+, as an ''energy propellant", substantially increased cellular bioenergetic levels to support the osteogenesis via the Akt-glycolysis-Mrs2-mitochondrial axis, and consequently enhanced the osteoinductivity of BMP-2. Based on the mechanistic discovery, microgel composite hydrogels were fabricated as low-dose BMP-2/Mg2+ codelivery system through microfluidic and 3D printing technologies. An in vivo study further confirmed that rapid and robust bone regeneration was induced by the codelivery system. Collectively, these results suggest that this bioenergetic-driven, cost-effective, low-dose BMP-2-based strategy has substantial potential for bone repair.