Size-optimized Ceria Nanoparticles Attenuate Intervertebral Disc Degeneration by Rescuing Nucleus Pulposus Cell Senescence via Reducing Oxidative Stress and Stimulating PI3K/AKT Pathway (PRJCA043215)

Intervertebral disc degeneration (IVDD), characterized by nucleus pulposus (NP) cell senescence and extracellular matrix (ECM) degradation, underlies numerous degenerative spinal disorders. Current clinical management remains limited. Here, we evaluate PEG600-coated ceria nanoparticles (CeNPs) of varying sizes (1.2, 4, and 40 nm) for mitigating NP cell senescence and IVDD in rats. The 4 nm-PEG600 CeNPs demonstrated superior therapeutic efficacy, attributable to reduced cytotoxicity and enhanced physiological stability within IVD tissue. Mechanistically, CeNPs attenuated IVDD by countering ROS accumulation-induced NP senescence, evidenced by ECM metabolism analysis, SASPs profiling, senescence and proliferation assay, mitochondrial function assessment. Crucially, beyond direct ROS scavenging, 4 nm-PEG600 suppressed senescence via AKT Ser473 phosphorylation in the PI3K-AKT pathway. These findings establish size-optimized CNPs as a promising dual-targeting (antioxidant/anti-senescence) IVDD therapeutic strategy.