Adenosine-grafted nanocomposite hydrogel coordinates immunoregulatory and regenerative remodeling at the tendon-bone interface

Abstract Regeneration of the tendon–bone interface after rotator cuff repair is challenged by persistent inflammation, limited vascularization and incomplete matrix restoration. Prior studies highlighted adenosine as a candidate for local repair. We then analyzed a public fracture-callus single-cell RNA-sequencing dataset and observed immune-related changes associated with adenosine treatment. On this basis, we developed an adenosine-grafted nanocomposite hydrogel to support local tissue repair. Adenosine was grafted onto dendritic mesoporous bioactive glass through an α-ketoglutarate linker to form dMBG-K-A, which was incorporated into a gelatin methacrylate/hyaluronic acid methacrylate (GelMA/HAMA) hydrogel, yielding dMKA@GH. In vitro, dMBG-K-A reduced M1-associated markers under lipopolysaccharide stimulation and enhanced M2-associated markers in separate interleukin-4/interleukin-13-induced cultures. It also promoted osteogenic differentiation of human bone marrow mesenchymal stem cells and endothelial tube formation. In a rat rotator cuff repair model, dMKA@GH increased bone formation, collagen deposition and proteoglycan-rich, COL-II-positive matrix at the repair interface. Lower iNOS staining and higher VEGF staining were observed at 4 weeks. At 8 weeks, the dMKA@GH group achieved a maximum load of 23.550 ± 1.907 N, exceeding that of the other groups. These findings support adenosine-grafted nanocomposite hydrogels as a local material strategy for improving tendon–bone healing. Graphical Abstract