A ROS and pH dual - responsive hydrogel-nanoparticle system restores intervertebral disc and alleviates related pain by modulating senescence and panoptosis of nucleus pulposus cells

Intervertebral disc degeneration (IVDD) is a common cause of low back pain (LBP). We developed a dual-responsive hydrogel-nanoparticle system (PCL5 system), incorporating PLGA-mPEG nanoparticles, boronate-modified dextran (ODex-ABA), catechol-functionalized quaternary ammonium chitosan (QCS-DOPA), and LbGP (Lycium barbarum glycopeptide) to address the progression of IVDD. The PCL5 system forms through dynamic Schiff base and boronate ester bonds, offering self-healing, injectability, and controlled drug release, responsive to ROS and pH changes. The PCL5 system effectively scavenges ROS, restores ECM homeostasis, and mitigates nucleus pulposus cells (NPCs) senescence and PANoptosis. In vivo, the PCL5 system has successfully maintained the disc height, alleviated ECM deterioration, and reduced the IVDD-related pain behaviors in animal models with different genetic backgrounds, and under various stimuli among aging and puncture. The PCL5 system mainly demonstrates its therapeutic potential for IVDD and pain by inhibiting ROS stress, suppressing the senescence and PANoptosis of NPCs. This work provides a promising biomaterial strategy for the treatment of IVDD and paves the way for advanced precision therapies in degenerative spinal diseases. • Developed a dual-responsive hydrogel-nanoparticle system for IVDD treatment. • PCL5 system scavenges ROS, restores ECM balance, and mitigates NPCs senescence. • PCL5 effectively alleviates IVDD-related pain and maintains disc height in vivo.