ROS-responsive Se@HSC-DIA enables local drug delivery and modulates CD44high inflammatory nucleus pulposus cell states in intervertebral disc degeneration

Low back pain is closely associated with structural abnormalities of the spine, yet how altered mechanical loading drives persistent disc inflammation and pain remains unclear. Here, we investigated the cellular mechanisms linking structural disturbance to intervertebral disc degeneration (IVDD) and developed a mechanism-guided local therapy. Human disc specimens from patients with lumbar spondylolysis (LS), integrated single-cell RNA-sequencing datasets, primary nucleus pulposus cells (NPCs), pharmacological perturbation, and an in vivo IVDD model were analyzed. LS-associated discs showed increased NOX4 and CD44 expression with enhanced oxidative stress and inflammation. Single-cell analysis identified a CD44 high inflammatory NP population (Inflamed NP) that expanded with degeneration severity. Oxidative stress promoted this state, whereas IL-1β-IL-1R1 signaling and canonical NF-κB activation sustained its inflammatory and matrix-catabolic phenotype. Drug screening identified diacerein (DIA) as an effective inhibitor of this axis. We therefore developed Se@HSC-DIA, an injectable hydrogel that responds to reactive oxygen species (ROS) and integrates CD44 affinity, ROS-triggered DIA release, and selenium nanoparticle-mediated antioxidant activity. Se@HSC-DIA reduced ROS, NF-κB activation, inflammatory mediators, and matrix catabolism in NPCs. In vivo, it preserved disc structure, restored matrix homeostasis, alleviated pain-related behavior, and shifted the degenerative transcriptome toward homeostasis without evident systemic toxicity. These findings define a ROS-IL-1β/IL-1R1-NF-κB axis linking structural stress to an inflammatory NP state and support microenvironment-responsive biomaterials for IVDD therapy.