Nanoparticle-Woven Stem Cells as Innovative Building Blocks for Enhanced 3D Bone Development and Tissue Regeneration

Several major issues in conventional 3D spheroid systems include cellular heterogeneity, uncontrolled cell differentiation, and batch-to-batch variations. In this study, mesoporous silica nanoparticles (mSiO₂ NPs), human adipose-derived mesenchymal stem cells (hADMSCs), and boronate-phenolic interactions are applied for the first time to address these issues. Stable attachment of the NPs to hADMSCs via boronate-phenolic interactions produced nanobiohybrids, a novel building block for 3D spheroids. The developed 3D spheroids demonstrated enhanced cell viability while maintaining their structural stability and improved uniform differentiation into bone tissue with reduced heterogeneity within the spheroids. Lastly, 6 weeks after transplanting nanobiohybrid-incorporated spheroids onto an <i>in vivo</i> mouse calvarial defect, the regenerated bone area was significantly enhanced. These findings indicate that nanobiohybrid-enabled spheroids represent a potential strategy to overcome the inherent limitations of conventional cell spheroids, providing a superior platform for the regeneration of various tissues.