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Guided by network pharmacology and docking, we prioritized the NF\u2010\u03baB\u2013LCN2 axis as a druggable target of wedelolactone (WDL). To achieve targeted modulation, we engineered a dual\u2010network ROS\u2010responsive hydrogel (WPG) in which a phenylboronic\u2010ester\/PVA redox\u2010cleavable network interpenetrates a covalently crosslinked GelMA\u2013elastin matrix, enabling mechanically robust yet stimulus\u2010triggered WDL release. WDL suppressed NF\u2010\u03baB activation and downregulated LCN2 in both macrophages and AF cells. Conditioned\u2010medium co\u2010culture demonstrated that WDL disrupts macrophage\u2010derived LCN2\u2010mediated paracrine amplification, breaking the self\u2010sustaining inflammatory loop. Bulk RNA\u2010seq across both cell types revealed coordinated downregulation of NF\u2010\u03baB \u2013 driven chemokine cascades and restoration of adhesion and ECM gene programs following WPG treatment. In a rat AF\u2010defect model, intradiscal WPG administration preserved disc height and T\n                    <jats:sub>2<\/jats:sub>\n                    \u2010weighted MRI signal, reduced MMP13 while increasing Collagen I and Aggrecan expression, suppressed nuclear P\u2010p65 and LCN2, and improved segment biomechanics\u2014without eliciting adverse hematological or organ responses. Collectively, these findings establish that aligning molecular targeting (NF\u2010\u03baB\u2013LCN2 modulation) with the pathophysiological context via ROS\u2010gated delivery provides a synergistic strategy for AF repair and attenuation of IVDD progression.\n                  <\/jats:p>","DOI":"10.1002\/advs.202521709","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T09:38:31Z","timestamp":1767605911000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["ROS\u2010Responsive Wedelolactone Hydrogel Promotes Intervertebral Disc Repair by Disrupting the NF\u2010\u03baB\u2013LCN2 Inflammatory Feedback Loop"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5535-6229","authenticated-orcid":false,"given":"Zimei","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Orthopedic Surgery The Seventh Affiliated Hospital of Sun Yat\u2010sen University  Shenzhen P. 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