Multi-omics-informed hydrogel design: modulating IL-6 to reduce endoplasmic reticulum stress in bone regeneration

Post-traumatic bone healing exhibits significant heterogeneity, especially in different injury sites. Notably, bone healing progresses more rapidly in alveolar bone defects compared to the slower repair process observed in femoral bone. Given this physiological phenomenon, understanding site-specific differences is crucial for designing functional biomaterials to enhance bone regeneration. This study, via multi-omics analysis, identified the pivotal role of high interleukin-6 (IL-6) expressing alternatively activated (M2) macrophages in early alveolar bone healing. It was found that IL-6 level in M2 macrophages could modulate heat shock protein family A member 5, alleviating endoplasmic reticulum stress (ERS) and preventing apoptosis, thereby promoting bone regeneration. Based on these findings, a gelatin-based porous hydrogel optimized for localized IL-6 delivery was further developed to accelerate bone healing in femoral defects. The results demonstrated that this hydrogel significantly enhanced femoral bone regeneration by modulating ERS and hematoma responses. These findings offer promising strategies for enhancing bone regeneration. • Multi-omics strategy advanced tailored material design. • Multi-omics analysis revealed IL-6's role in alveolar bone healing. • IL-6 in M2 macrophages alleviated ERS and prevented apoptosis. • Gelatin-based hydrogel was optimized for localized IL-6 delivery. • Hydrogel enhanced femoral bone regeneration by modulating ERS.