Stem Cells Recruited from Multifunctional Tetrahedral Framework Nucleic Acids Induce Vascularized Osteogenesis to Repair Bone Defects

Abstract Repairing and reconstructing massive bone defects remains a critical clinical challenge. Recruiting early stem cells, and promoting their angiogenesis and osteogenesis are crucial for the initiation of efficient in situ bone regeneration and repair. This study aims to promote bone regeneration and reconstruct massive bone defects using tetrahedral framework nucleic acids (tFNAs) with Apt19S, microRNA‐21 (miR21), and bone morphogenetic protein 2 (BMP2) (Apt19S‐tFNAs‐miR21/BMP2 [ATMB]). ATMB promotes the proliferation, migration, and recruitment of bone mesenchymal stem cells (BMSCs), alkaline phosphatase activity, and osteogenesis‐related mRNAs and proteins in vitro. The angiogenesis‐related genes and proteins of HUVECs are effectively enhanced by ATMB. Furthermore, chitosan hydrogel fills bone defects and extends the duration of drug action, combining with ATMB to form ATMCB. ATMCB is highly efficient at recruiting BMSCs, matrix mineralization, and new bone formation in rat calvarial defects of critical size in vivo. This study demonstrates a promising in situ bone regeneration approach for bone defect repair that overcomes the traditional limitations of cell‐delivery therapy.