Edaravone-based precision antioxidative therapy alleviates intervertebral disc degeneration via the Nrf2/Aldh3a1 axis

Oxidative stress-induced dysfunction of nucleus pulposus (NP) cells is a key driver of intervertebral disc degeneration (IDD), promoting accelerated cellular senescence and extracellular matrix (ECM) degradation. Moreover, effective regulation of redox homeostasis within the avascular intervertebral disc remains challenging due to rapid drug clearance and poor targeting. To address these issues, we developed a precision antioxidative therapeutic strategy by integrating edaravone (ED), an FDA-approved free radical scavenger, into a novel reactive oxygen species (ROS)-responsive hydrogel (ED@HFA) for localized intradiscal delivery. Mechanistically, ED restored redox balance and preserved ECM homeostasis in NP cells under oxidative stress by activating the Nrf2/Aldh3a1 signaling axis. From a delivery perspective, ED@HFA employs hyaluronic acid methacrylate (HAMA) as a biomimetic matrix and incorporates 3-fluorophenylboronic acid (FPBA) to construct a redox-sensitive crosslinked network. The electron-withdrawing fluorine substituent in FPBA markedly enhances responsiveness to pathological ROS levels for on-demand drug release. In a puncture-induced rat IDD model, this delivery system effectively preserved disc structural integrity and attenuated IDD progression. Collectively, this precision antioxidative delivery platform, combining the safe and effective antioxidant ED with a novel ROS-responsive hydrogel, provides a promising therapeutic approach for the treatment of IDD.