Sensory Nerve Regulation via H3K27 Demethylation Revealed in Akermanite Composite Microspheres Repairing Maxillofacial Bone Defect

Maxillofacial bone defects exhibit intricate anatomy and irregular morphology, presenting challenges for effective treatment. This study aimed to address these challenges by developing an injectable bioactive composite microsphere, termed D‐P‐Ak (polydopamine‐PLGA‐akermanite), designed to fit within the defect site while minimizing injury. The D‐P‐Ak microspheres biodegraded gradually, releasing calcium, magnesium, and silicon ions, which, notably, not only directly stimulated the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) but also activated sensory nerve cells to secrete calcitonin gene‐related peptide (CGRP), a key factor in bone repair. Moreover, the released CGRP enhanced the osteogenic differentiation of BMSCs through epigenetic methylation modification. Specifically, inhibition of EZH2 and enhancement of KDM6A reduced the trimethylation level of histone 3 at lysine 27 (H3K27), thereby activating the transcription of osteogenic genes such as Runx2 and Osx. The efficacy of the bioactive microspheres in bone repair is validated in a rat mandibular defect model, demonstrating that peripheral nerve response facilitates bone regeneration through epigenetic modification. These findings illuminated a novel strategy for constructing neuroactive osteo‐inductive biomaterials with potential for further clinical applications. Injectable polydopamine‐PLGA‐Akermanite composite microspheres biodegrades to produce bioactive ions, promoting bone regeneration in irregular maxillofacial defects. Specifically, D‐P‐Ak microspheres activate the trigeminal nerve to release CGRP, synergistically enhancing the osteogenic gene transcription of BMSCs. In detail, CGRP intervenes the KDM6A‐EZH2 balance and causes H3K27 demethylation at an epigenetic level, proving the peripheral nerve regulation in bone repairing.