Nanosized silicon nitride promotes vascularized osteogenesis through regulating the endothelial adherens junctions via the FRMD6/VE-cadherin pathway.

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.