An injectable hydrogel loaded with miRNA nanocarriers promotes vessel-associated osteoclast (VAO)-mediated angiogenesis and bone regeneration in osteonecrosis of the rat femoral head.

Osteonecrosis of the femoral head (ONFH) remains a significant clinical challenge. Despite various strategies aimed at promoting bone repair and halting disease progression, an effective cure remains elusive. Recent studies have identified a non-bone-resorbing osteoclast subtype, vessel-associated osteoclasts (VAOs), distinct from classical bone-associated osteoclasts (BAOs), offering new therapeutic opportunities for ONFH. Notably, we observed alterations in the populations and distributions of VAOs and BAOs in the femoral head of ONFH patients, suggesting that the imbalance between these two osteoclast subtypes contributes to ONFH pathology. Here, we developed an injectable alginate/hydroxyapatite hydrogel (AHH) loaded with graphene oxide-based miR-7b nanocarriers (GPC@miR) for ONFH treatment. The controlled release of GPC@miR from AHH/GPC@miR inhibited BAO formation by suppressing dendritic cell-specific transmembrane protein (DC-STAMP), thereby reducing bone resorption. Meanwhile, mono-/bi-nucleated VAOs were preserved and increased in number, promoting angiogenesis of type H vessels and osteogenesis via platelet-derived growth factor-BB (PDGF-BB) and vascular endothelial growth factor-A (VEGF-A) secretion. Intraosseous administration of AHH/GPC@miR rebalanced VAOs and BAOs, restored the femoral head microenvironment, and enhanced vascularization and bone regeneration in ONFH rat models. This study introduces a novel biomaterial-based strategy for ONFH repair by regulating osteoclast subtypes, providing insights into VAO-mediated angiogenesis and osteogenesis for bone regeneration.