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

## TL;DR

A responsive hydrogel delivers wedelolactone to treat disc degeneration by targeting an inflammatory loop, restoring disc structure and function in rats.

## Contribution

A ROS-responsive hydrogel is developed to specifically target the NF-κB–LCN2 inflammatory feedback loop for intervertebral disc repair.

## Key findings

- WPG treatment suppressed NF-κB activation and LCN2 in macrophages and AF cells.
- WPG preserved disc height and MRI signal while improving biomechanics in a rat model.
- RNA-seq showed restoration of ECM genes and downregulation of inflammatory pathways.

## 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 T2‐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.

A mechanically robust, ROS‐responsive hydrogel is engineered to treat intervertebral disc degeneration by targeting the NF‐κB–LCN2 inflammatory feedback loop. By delivering wedelolactone specifically within oxidative niches, this system disrupts macrophage–disc cell crosstalk. This “pathology‐triggered” strategy restores extracellular matrix homeostasis, preserves disc structure, and recovers biomechanical function in vivo.