Composite hydrogel modulates regulatory T cell-mediated osteoimmunomodulatory osteogenesis for steroid-induced osteonecrosis of the femoral head

• In this study, the regulation of regulatory T cells (T regs ) was used as a new target for repairing SONFH bone defects. • MS IL-2 /nHA@Gel CCL22 could release CCL22 and IL-2 to recruit and activate T regs , which improved the osteoimmune microenvironment in osteonecrotic regions and promoted macrophage M2 polarization, BMSCs osteogenic differentiation, and HUVECs vascularization. • In a rabbit SONFH model, MS IL-2 /nHA@Gel CCL22 mobilized T reg homing and aided femoral head repair. Steroid-induced osteonecrosis of the femoral head (SONFH) is a prevalent condition in clinical settings, often leading to femoral head collapse without timely intervention, necessitating total hip arthroplasty (THA). However, THA carries significant financial costs and substantial risks. Drilling and decompression combined with autologous bone grafting are widely utilized to treat early-stage SONFH. Nevertheless, the drawbacks of autologous bone graft harvesting limit its clinical utility. Many studies have sought to replace autologous grafts with biomaterials to mitigate these adverse effects. However, the role of regulatory T cells (T regs ) in the osteonecrotic region is often ignored. The reduced quantity and impaired function of T regs in the osteonecrotic region hinder the T reg -mediated osteogenic differentiation of BMSCs and M2 polarization of macrophages, disrupting the immune microenvironment and stalling bone repair. We prepared an injectable functionalized hydrogel (MS IL-2 /nHA@Gel CCL22 ), capable of releasing CCL22 and IL-2 to recruit T regs , and activate them via the JAK3/STAT5/Foxp3 pathway. This intervention promoted macrophage M2 polarization, osteogenic differentiation of BMSCs, and vascularization of HUVECs. In a rabbit SONFH model, implantation of MS IL-2 /nHA@Gel CCL22 successfully mobilized T reg homing, stimulated osteogenesis and angiogenesis, and facilitated femoral head repair. In summary, MS IL-2 /nHA@Gel CCL22 effectively recruits and activates T regs , enhancing osteoimmunomodulatory processes to repair SONFH.