Dynamic modulation of immune-neural axis via controlled magnesium-releasing nanocapsules accelerates cranial bone regeneration.

Critical-sized cranial defects present a significant challenge in the field of bone tissue regeneration. Despite the emergence of various approaches to promote new bone formation, the clinical outcomes remain suboptimal. In this study, we developed an inorganic-organic hybrid bioink suitable for 3D printing of photocurable scaffolds. This bioink incorporates our novel nanocapsules with a shell consisting of amorphous whitlockite and PEG coating, which endows the scaffolds with superior mechanical strength and pro-osteogenic capacity. These nanocapsules enable a dual-phase Mg2+ release profile to facilitate the initial pro-inflammatory activation of human THP-1-derived macrophages and their seamless transition to a pro-regenerative phenotype. We further showed that this dynamic Mg2+ delivery strategy significantly outperformed traditional sustained-release approaches in supporting cranial bone regeneration in a rat critical-sized cranial defect model. Moreover, with evidence from trigeminal ganglia in rat model and in vitro studies using MED17.11-derived sensory neurons, we showed the controlled immunomodulation through this tailored Mg2+ delivery more closely mimics the natural healing process, promoting the activation of sensory nerves, which is essential for effective bone regeneration. Overall, our study demonstrated the potential of our nanocapsules as a cost-effective approach for the dynamic modulation of the immune-neural axis, offering valuable insights for the future design of bioactive materials for cranial bone regeneration.