ADGRG1-targeted hypoxia preconditioned extracellular vesicles ameliorate intervertebral disc degeneration by delivering taurine to disrupt the oxidative stress feedback loop-driven ferroptosis in nucleus pulposus cells

Cervical spondylosis and low back pain caused by intervertebral disc degeneration (IVDD) are among the leading causes of clinical disability. Although excessive reactive oxygen species (ROS) are established drivers of IVDD, the mechanisms linking ROS accumulation to disc cell dysfunction, cell death programs, and disruption of intervertebral disc tissue homeostasis remain insufficiently elucidated, limiting the development of effective redox-targeted therapies. Here, we revealed the "ROS-Mitochondrial dysfunction-Ferritinophagy" oxidative stress feedback loop serves as the central mechanism driving ROS-induced nucleus pulposus cell (NPC) ferroptosis to promote IVDD progression. Furthermore, we identified the membrane protein ADGRG1 as a biomarker of ROS-induced ferroptosis in injured NPCs and developed ADGRG1-tethered peptide (A1TP)-modified hypoxia preconditioned extracellular vesicles (HX-EVs) with targeted antioxidant therapeutic potential. The engineered HX-EVs selectively accumulated in injured NPCs and delivered high levels of taurine, which bound to LKB1 (Glu165, Arg301) and MO25 (Arg194, Leu197) residues to facilitate the assembly of the LKB1-STRAD-MO25 kinase complex. This interaction regulated the expression of NCOA4 and TFAM by activating the AMPK/NRF2 signaling pathway, which suppressed ferritinophagy, enhanced mitochondrial repair and regeneration, and protected NPCs from ROS-induced ferroptosis, ultimately facilitating the repair of degenerated intervertebral discs. In summary, the A1TP-HX-EV system developed in this study provides a promising theranostic application for IVDD and offers valuable insights into the mechanisms of targeted HX-EV delivery and intervertebral disc regeneration. Schematic diagram depicting the therapeutic effects of A1TP-HX-EVs for IVDD treatment. The oxidative stress-induced positive feedback loop driven by “ROS-mitochondrial dysfunction-ferritinophagy” serves as a crucial pathogenic mechanism in IVDD. A1TP-HX-EVs exhibit a selective targeting tendency to the injured NPCs with an enhanced NP protection effect by taurine delivery. A1TP-HX-EVs protected against oxidative stress feedback loop-driven NPCs ferroptosis by facilitating the assembly of the LKB1-STRAD-MO25 kinase complex to activate the AMPK/NRF2 signaling pathway, and further suppressing ferritinophagy and enhancing mitochondrial repair and regeneration. • Oxidative stress–induced NPC ferroptosis is driven by a ROS-mitochondrial dysfunction-ferritinophagy positive feedback loop in IVDD. • ADGRG1 is a biomarker of ROS-induced NPC ferroptosis; its expression in nucleus pulposus tissue aids IVDD diagnosis. • A1TP-HX-EVs ameliorate IVDD by targeted delivery of high levels of taurine to degenerative NPCs. • Taurine promotes LKB1–STRAD–MO25 complex assembly, activating AMPK/NRF2 pathway and disrupting oxidative stress feedback loop. • This model paves the way for intervertebral disc protection and therapeutic effects of HX-EVs through targeted inhibition of ferroptosis.