Modulating trained immunity while simultaneously initiating regenerative cues presents a significant challenge in large bone defect therapy. This study introduces a cell-free approach utilizing a 3D microenvironment-responsive scaffold to orchestrate immune reprogramming. To mitigate maladaptive trained immunity and activate regenerative signaling, a composite fibrous scaffold is functionalized with immune-engineered exosomes derived from inflammation-primed mesenchymal stem cells (PSS-iEXO) in a reactive oxygen species (ROS)-responsive manner. The PSS-iEXO scaffolds incorporate boronic ester linkages as ROS-sensitive moieties, enabling rapid, dynamic, and “on-demand” exosome release in response to elevated ROS levels characteristic of the early inflammatory phase post-injury, thereby initiating regeneration. In vitro and in vivo analyses reveal that these scaffolds precisely target and modulate maladaptive trained immunity, reprogramming immune responses by shifting macrophage polarization from a hyperactivated type I phenotype to a balanced state while promoting CD4+ regulatory T cell activation—both critical for coupling angiogenesis and osteogenesis. Mechanistic insights highlight the role of engineered exosomes in enhancing mitochondrial function and oxidative phosphorylation in macrophages, establishing a cell-free immune-regenerative niche for large bone defect therapy. Schematic diagram of the fabrication, function, and mechanism of ROS-responsive 3D electrospun nanofiber scaffolds loaded with immunoengineered exosomes (PSS-iEXO) for promoting large bone repair.