A Redox Homeostasis Modulatory Hydrogel with GLRX3⁺ Extracellular Vesicles Attenuates Disc Degeneration by Suppressing Nucleus Pulposus Cell Senescence

Characterized by nucleus pulposus (NP) cell senescenceand extracellularmatrix (ECM) degradation, disc degeneration is a common pathologyfor various degenerative spinal disorders. To date, effective treatmentsfor disc degeneration are absent. Here, we found that Glutaredoxin3(GLRX3) is an important redox-regulating molecule associated withNP cell senescence and disc degeneration. Using a hypoxic preconditioningmethod, we developed GLRX3(+) mesenchymal stem cell-derivedextracellular vehicles (EVs-GLRX3), which enhanced the cellular antioxidantdefense, thus preventing reactive oxygen species (ROS) accumulationand senescence cascade expansion in vitro. Further,a disc tissue-like biopolymer-based supramolecular hydrogel, whichwas injectable, degradable, and ROS-responsive, was proposed to deliverEVs-GLRX3 for treating disc degeneration. Using a rat model of discdegeneration, we demonstrated that the EVs-GLRX3-loaded hydrogel attenuatedmitochondrial damage, alleviated the NP senescence state, and restoredECM deposition by modulating the redox homeostasis. Our findings suggestedthat modulation of redox homeostasis in the disc can rejuvenate NPcell senescence and thus attenuate disc degeneration.