A xenogeneic developmental matrix hydrogel with MnO2-gallic acid enables spatiotemporal immunometabolic reprogramming and endochondral bone repair in steroid-associated osteonecrosis.

Steroid-associated osteonecrosis (SON) is characterized by a refractory bone defect microenvironment involving oxidative stress, persistent inflammation, and impaired vascularization, which limits the efficacy of conventional graft materials. Here, we developed a temporally programmable composite hydrogel, GelMA/dECM@MnO2-GA, by integrating human induced pluripotent stem cell (iPSC)-derived decellularized extracellular matrix (iPSC-dECM) with an MnO2-gallic acid (GA) reactive oxygen species (ROS)-responsive module. Following implantation, elevated ROS may induce the release of MnO2 and GA, which was associated with ROS scavenging, alleviation of local hypoxia, and attenuation of inflammatory signaling. This early redox modulation was accompanied by a shift in macrophage polarization from M1 toward the M2 phenotype, together with increasing regulatory T cell (Treg) enrichment. Our findings further suggest that CCL22-mediated Treg recruitment via the CCR4-PI3K/AKT axis may contribute to Treg survival and migration, reinforce M2 polarization, and help sustain a pro-regenerative osteoimmune microenvironment. At later stages, the retained iPSC-dECM served as a developmental matrix template to guide host progenitor cells through an endochondral ossification-like process, while enhanced H-type vessel formation was associated with coupled angiogenesis and osteogenesis. In a rat steroid-induced femoral defect model, GelMA/dECM@MnO2-GA significantly promoted bone regeneration and reduced the local expression of IL-1β, IL-6, and TNF-α. Transcriptomic and functional analyses supported an association between GelMA/dECM@MnO2-GA treatment, coordinated M2 macrophage polarization, Treg enrichment, and improved bone repair. Collectively, these findings suggest that this spatiotemporally orchestrated hydrogel may provide a promising strategy for overcoming the hostile microenvironment of steroid-associated bone defects, with potential relevance to other refractory osteonecrotic conditions.