Engineered senescence-targeting apoptotic extracellular vesicles-laden injectable hydrogel microspheres mitigating nucleus pulposus cell ferroptosis against intervertebral disc degeneration.

As the rapid growth of aging population, intervertebral disc degeneration (IVDD) becomes a prevalent degenerative disorder in clinical practice. Ferroptosis-induced senescence in nucleus pulposus cells (NPCs) represents a primary pathological mechanism underlying IVDD. Strategies for reducing ferroptosis to delay NPC senescence hold prospects for therapeutic advances. According to previously reported proteomic profiles of apoptotic extracellular vesicles (ApoEVs), we noticed that most key ferroptosis-regulating proteins were identified in the ApoEVs proteome, including upregulation of Glutathione Peroxidase 4 (GPX4). In this study, we developed injectable hydrogel microspheres (HMs) integrating with senescent NPC-targeting ApoEVs as GPX4 delivery vehicle and anti-inflammatory diclofenac sodium (DFS) for IVDD treatment. The effect of ApoEVs on reducing NPC ferroptosis and reversing NPC senescence-related metabolic dysfunction and damage was reinforced through modification of reactive oxygen species (ROS) responsive and senescent NPC-targeting peptide. In vivo experiments and single cell RNA sequencing analysis elucidated that the senescence-targeted system significantly attenuated ferroptosis and inflammatory pathways, and prevented the transformation of inflammatory NPC phenotypes, thereby offering opportunities for reducing senescent NPCs from ferroptosis and mitigating IVDD progression.