Nanosized silicon nitride promotes vascularized osteogenesis through regulating the endothelial adherens junctions...

Effective vascularization is critical for successful bone regeneration. Herein, silicon nitride nanoparticles (Si₃N₄ NPs) were demonstrated to enhance early vascular regeneration and promote new bone formation in vivo. We found that Si₃N₄ NPs induced autophagy and stimulated angiogenesis after they were uptaken by human umbilical vein endothelial cells (HUVECs). Transcriptome sequencing revealed that the angiogenic effect of Si₃N₄ NPs was closely associated with modulation of adherens junctions (AJs). Specifically, Si₃N₄ NPs significantly increased phosphorylation of the core AJs protein VE-cadherin in HUVECs, thereby inducing AJs dissociation-a crucial step in angiogenesis initiation. Furthermore, FRMD6 was identified as the most significantly altered upstream regulator. Knockdown of FRMD6 in endothelial cells restored AJs stability and abolished the Si₃N₄ NP-mediated pro-angiogenic effects. Local FRMD6 knockdown also impaired the ability of Si₃N₄ NPs to promote neovascularization and bone regeneration in the rat calvarial defect model. These findings suggest that Si₃N₄ NPs promote angiogenesis via the FRMD6/VE-cadherin pathway. This mechanistic insight provides a foundation for the development of nanosized Si₃N₄-based tissue engineering strategies.