Functional Injectable Hydrogel for Bone Regeneration: Regulation of the circSRPK1/miR‐320a Axis and Targeting Multiple Osteogenic Pathways via <i>CDH2</i> and <i>Osterix</i> Genes

ABSTRACT Hydrogels loaded with microRNA (miRNA) have shown promise in bone‐defect repair. Here, we present the first report of miRNA‐loaded hydrogels containing bioactivities to treat steroid‐induced osteonecrosis of the femoral head (SONFH), based on the mechanism of competing endogenous RNAs. Transcriptome sequencing of human bone marrow mesenchymal stem cells (HBMSCs) extracted from the proximal femoral bone marrow and subsequent functional assays revealed that the circSRPK1/miR‐320a axis promotes HBMSCs osteogenic differentiation. By incorporating antagomir‐320a (a miR‐320a inhibitor) encapsulated in liposomes into injectable hyaluronic acid (HA) hydrogels, we constructed an injectable hydrogel, HA@antagomir‐320a. This hydrogel demonstrated exceptional osteogenic properties, targeting multiple osteogenic pathways via CDH2 and Osterix and exhibited excellent in vitro biocompatibility. In vivo, it substantially enhanced bone formation in the osteonecrotic area of the femoral head. This injectable HA@antagomir‐320a hydrogel, which exhibited exceptional biocompatibility and osteogenic properties in vivo and in vitro, offers a promising and minimally invasive solution for the treatment of SONFH.