Mineralized DNA tetrahedron-structured hydrogels: a dual-functional Scaffold for immunomodulation and bone regeneration

Clinical limitations of autografts and allografts have driven advances in bone tissue engineering. Emerging biomaterials offer tunable mechanical and bio-regenerative properties for bone reconstruction. DNA hydrogels have attracted increasing attention due to their extracellular matrix-like architecture and excellent cargo-loading capacity. However, their rapid degradation and limited immunomodulatory activity have hindered their long-term efficacy in bone regeneration. To address these limitations, a mineralized tetrahedral framework nucleic acids (tFNAs) hydrogel (Cap-gel) was engineered to integrate early immunoregulation with sustained osteogenic activity. The stable and programmable spatial structure of tFNAs not only promotes macrophage polarization toward the M2 phenotype by presenting immunomodulatory ligands but also serves as a nucleation template for calcium phosphate crystallization, leading to the formation of nano-mineralized structures with controlled morphology. In vitro, Cap-gel promoted osteogenic differentiation via both immune-dependent and independent pathways, while in vivo, it modulated early immune responses and accelerated bone regeneration in a calvarial defect model. In summary, this study introduces a novel tFNA-based mineralized DNA hydrogel system that integrates immunomodulation and osteogenesis, providing a promising strategy for enhanced bone repair in tissue engineering applications. A mineralized DNA hydrogel is constructed by sticky-end self-assembly of tetrahedral framework nucleic acids followed by calcium-phosphate deposition. The hydrogel exhibits antioxidant, immunomodulatory, and osteoinductive properties, enabling sequential regulation of the bone healing microenvironment and effectively promoting cranial defect regeneration.