ROS‐Responsive Wedelolactone Hydrogel Promotes Intervertebral Disc Repair by Disrupting the NF‐κB–LCN2 Inflammatory Feedback Loop

ABSTRACT Intervertebral disc degeneration (IVDD) is driven by persistent inflammation–oxidative stress that disrupts annulus fibrosus (AF) homeostasis. Guided by network pharmacology and docking, we prioritized the NF‐κB–LCN2 axis as a druggable target of wedelolactone (WDL). To achieve targeted modulation, we engineered a dual‐network ROS‐responsive hydrogel (WPG) in which a phenylboronic‐ester/PVA redox‐cleavable network interpenetrates a covalently crosslinked GelMA–elastin matrix, enabling mechanically robust yet stimulus‐triggered WDL release. WDL suppressed NF‐κB activation and downregulated LCN2 in both macrophages and AF cells. Conditioned‐medium co‐culture demonstrated that WDL disrupts macrophage‐derived LCN2‐mediated paracrine amplification, breaking the self‐sustaining inflammatory loop. Bulk RNA‐seq across both cell types revealed coordinated downregulation of NF‐κB – driven chemokine cascades and restoration of adhesion and ECM gene programs following WPG treatment. In a rat AF‐defect model, intradiscal WPG administration preserved disc height and T 2 ‐weighted MRI signal, reduced MMP13 while increasing Collagen I and Aggrecan expression, suppressed nuclear P‐p65 and LCN2, and improved segment biomechanics—without eliciting adverse hematological or organ responses. Collectively, these findings establish that aligning molecular targeting (NF‐κB–LCN2 modulation) with the pathophysiological context via ROS‐gated delivery provides a synergistic strategy for AF repair and attenuation of IVDD progression.