Intervertebral disc degeneration (IDD) is a predominant contributor to spinal disorders. Previous studies have indicated that ferroptosis-induced senescence of nucleus pulposus cells (NPC) plays a critical role in IDD pathogenesis. This underscores therapeutic strategies aimed at inhibiting ferroptosis and delaying NPC senescence. Mesenchymal stem cell-derived exosomes (MSC-EVs), serving as a form of regenerative nanotherapy, inherit parental biological properties. In this study, we pretreated MSCs by simulating a senescent microenvironment to obtain “domesticated vesicles” (D-EVs) with enhanced targeting and anti-senescence properties. Multi-omics analysis revealed that D-EVs are enriched with GPX4 protein and achieve specific binding to senescent NPCs via the CXCL10-CXCR3 chemokine axis. Functionally, D-EVs delivered GPX4 protein to recipient NPCs, thereby inhibiting ferroptosis and alleviating cellular senescence. To enable sustained and on-demand release within the degenerative microenvironment, we anchored D-EVs to thermosensitive hydrogel via ROS-responsive peptides. This ROS-responsive hydrogel further potentiated D-EVs' efficacy in alleviating NPC ferroptosis and reversing senescence-associated metabolic dysfunction. Both in vitro and in vivo experiments revealed that this senescence-targeting system significantly suppresses ferroptosis and senescence pathways, and prevents conversion of the senescence phenotype in NPCs. This study presents a novel approach to inhibit ferroptosis, thereby delaying NPC senescence and mitigating IDD progression. • A “microenvironmental education” strategy preconditions MSCs using a senescence-mimicking niche. This yields D-EVs with high targeting specificity for senescent NPCs, mediated by the CXCL10-CXCR3 chemokine axis for IDD therapy. • Integrated multi-omics and functional studies identify GPX4 as a key anti-ferroptotic cargo in D-EVs. Act as a natural nano-delivery system, D-EVs directly transfer functional GPX4 protein into senescent NPCs, quenching lipid peroxidation and breaking the cycle linking ferroptosis to senescence. • An injectable, thermosensitive, and ROS-responsive hydrogel (D-EVs@Gel ROS ) is developed for on-demand delivery. This smart platform ensures sustained local retention and enables spatiotemporally controlled release of D-EVs, triggered specifically by pathological ROS in degenerative intervertebral discs. • The D-EVs@Gel ROS system demonstrates synergistic therapeutic effects in a rat IDD model. It effectively alleviates cellular senescence, inhibits ferroptosis, restores ECM homeostasis, and promotes structural and functional NP regeneration, as validated by MRI, histology, and molecular biomarkers.
Wu et al. (Thu,) studied this question.