Bone tissue engineering based on sustained release of MiR29c-modified framework nucleic acids from an injectable hydrogel

Bone defects affect the daily activities of patients and are prevalent complications of various skeletal disorders. The miR29 family regulates bone physiology and pathological processes. MiR29c can inhibit Dickkopf-1 (DKK1) expression, up-regulate the Wnt-signaling pathway, and modify the intracellular microenvironment. However, its application is hindered by poor stability and low bioavailability. This study sought to optimize the nano miR29c delivery system, enable enhanced drug effects, stable drug in situ retention, and sustained drug release. Tetrahedral framework nucleic acids (tFNAs), which have excellent drug-loading ability, endocytic capacity, and stability, were used with sticky ends to deliver miR29c (i.e., stFNAs-miR29c). Porous gelatin methacryloyl (GelMA) was selected as a scaffold for the in situ sustained release of stFNAs-miR29c and to provide a growth environment for bone marrow mesenchymal stem cells (BMSCs). This research developed a miR29c sustained-release system in situ: GelMA-stFNAs-miR29c and demonstrated its osteogenesis in vitro and in vivo. GelMA, stFNAs, and miR29c can function synergistically at nano-, micro-, and macro- scales that achieves high stability and efficiency on microRNA nano-delivery, regulates the local microenvironment, maintains the macro-osteogenic space, accelerates the osteogenic process, and ensures excellent osteogenesis effects, contributing to the broader application of miRNAs in biomedicine and improved bone regeneration in situ.