A xenogeneic developmental matrix hydrogel with MnO₂-gallic acid enables spatiotemporal immunometabolic reprogramming...

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.