Engineering a quercetin-greigite nanozyme-integrated UV-crosslinked hydrogel with antioxidant and anti-inflammatory properties for treating oxidative stress-driven intervertebral disc degeneration

Engineering bioresponsive materials for treating oxidative stress-induced degeneration remains a major challenge in intervertebral disc repair. We developed a UV-crosslinked injectable hydrogel composed of oxidized hyaluronic acid (OHA), gelatin, and polyethylene glycol diacrylate (PEGDA), co-loaded with quercetin and greigite nanozymes (G-NZ), termed OGPQ/G-NZ. This hydrogel exhibits robust structural integrity, shear resistance, and pH/reactive oxygen species (ROS)-responsive release of quercetin. G-NZ provides multi-enzyme–mimetic antioxidant activity, including superoxide dismutase, catalase, and glutathione peroxidase–like functions, along with antibacterial protection. In vitro, the hydrogel maintains nucleus pulposus cell (NPC) viability under oxidative conditions, reduces ROS accumulation, and promotes extracellular matrix (ECM) protein synthesis. In vivo application in a rat intervertebral disc degeneration (IVDD) model significantly preserved disc height, structure, and ECM integrity. RNA-seq and network pharmacology analysis identified PUM1/2-mediated degradation of E2F3 as a key regulatory pathway. Quercetin inhibits PUM1/2 expression, thereby stabilizing E2F3 mRNA and suppressing NPC senescence. Moreover, in vitro assays and CellChat-based single-cell analysis demonstrated that OGPQ/G-NZ modulates inflammatory macrophage polarization and enhances M2–NPC reparative signaling. These results highlight the hydrogel's engineered antioxidant and transcriptome-modulating properties as a promising platform for oxidative stress-responsive IVDD treatment.