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Intervertebral disc degeneration (IDD) is a major cause of spinal disorders. Previous studies have shown that ferroptosis-induced nucleus pulposus cell (NPC) senescence plays a key role in the pathogenesis of IDD. This emphasizes therapeutic strategies aimed at inhibiting ferroptosis and delaying NPC senescence. Mesenchymal stem cell-derived exosomes (MSC-EVs), as a regenerative nanotherapy, inherit the biological properties of their parent cells. In this study, MSCs were preconditioned by simulating an aging microenvironment to obtain "trained vesicles" (D-EVs) with enhanced targeting and anti-senescence properties. Multi-omics analysis showed that D-EVs are rich in GPX4 protein and specifically target senescent NPCs through the CXCL10-CXCR3 chemokine axis. Functionally, D-EVs deliver GPX4 protein to receptor NPCs, thereby inhibiting ferroptosis and alleviating cellular senescence. To achieve sustained and on-demand release in the degenerative microenvironment, D-EVs were anchored on a thermosensitive hydrogel via ROS-responsive peptides. This ROS-responsive hydrogel further enhances the efficacy of D-EVs in mitigating NPC ferroptosis and reversing senescence-related metabolic dysfunction. Both in vitro and in vivo experiments demonstrated that this senescence-targeted system significantly suppresses ferroptosis and senescence pathways and prevents the phenotypic transition of NPC senescence. This study proposes a novel approach to inhibit ferroptosis, thereby delaying NPC senescence and alleviating the progression of IDD.
Summary :
A study published in Bioactive Materials developed an intelligent delivery system (D-EVs@GelROS) combining microenvironment-trained mesenchymal stem cell-derived exosomes (D-EVs) and ROS-responsive hydrogel for targeted intervertebral disc degeneration (IDD) therapy. The team first trained MSCs using conditioned medium from senescent nucleus pulposus cells (NPCs) to obtain D-EVs with enhanced targeting and anti-senescence effects. Multi-omics analysis revealed that D-EVs specifically recognize and internalize senescent NPCs via the CXCL10-CXCR3 chemokine axis and enrich the key ferroptosis inhibitor GPX4. Functionally, D-EVs deliver GPX4 to inhibit lipid peroxidation, block ferroptosis-driven senescence, and restore NPC proliferation and extracellular matrix (ECM) synthesis.
To achieve controlled release in the degenerative microenvironment, a thermosensitive and ROS-responsive peptide-crosslinked hydrogel (GelROS) was used to encapsulate D-EVs (D-EVs@GelROS). This system enables responsive release in the high-ROS IDD environment, prolonging D-EV retention while maintaining bioactivity and targeting. In a rat IDD model, D-EVs@GelROS effectively suppressed senescence and ferroptosis markers, restored NP structural integrity, and improved ECM metabolism by upregulating GPX4 and COL2, significantly delaying degeneration. This "training-targeting-controlled release" strategy provides a novel paradigm for targeting the ferroptosis-senescence axis in IDD therapy.
Reference News:
DOI: 10.1016/j.bioactmat.2026.02.030
