Neuronal Sensitization Drives Bone Regeneration via Energy Metabolism and BMP2‐ErbB1 Signaling

ABSTRACT

High‐dose BMP2 can regenerate bone but is limited by dose‐dependent adverse events, whereas low doses often fail to produce robust repair. Here, we propose a regenerative strategy that expands the BMP2 therapeutic window by recruiting peripheral neurons as a biological amplifier of graft function. We engineered an injectable, self‐setting, magnesium‐doped bioactive glass cement (Mg‐BMP2@P‐BC) that co‐delivers Mg ^{2 +} and low‐dose BMP2 through dual encapsulation within PLGA microspheres and a bone‐cement matrix. This system augments neuronal mitochondrial bioenergetics and sensitizes BMP signaling in neuronal cells, thereby triggering the paracrine release of pro‐osteogenic neurotrophic factors and neuropeptides. Conditioned media from sensitized neurons enhance osteogenic differentiation of human mesenchymal stromal cells and angiogenic responses of endothelial cells. Multi‐omics analyses converge on metabolic rewiring and an Src‐centered signaling network consistent with growth‐factor sensitization. In a rabbit critical‐sized femoral‐condyle defect, the cement supports centripetal bone ingrowth and integration with host bone while markedly reducing heterotopic ossification. These findings demonstrate that neuronal sensitization offers a mechanistically grounded and translational approach to convert low‐dose BMP2 into amplified neuro‐vascular‐osteogenic cues for safer and more effective bone regeneration.