Size-optimized ceria nanoparticles attenuate intervertebral disc degeneration by rescuing nucleus pulposus cell senescence via reducing oxidative stress and stimulating PI3K/AKT pathway.

Intervertebral disc degeneration (IVDD), a condition characterized by nucleus pulposus (NP) cell senescence and extracellular matrix (ECM) degradation, is a major cause of degenerative spinal disorders. Current clinical management remains limited. In this study, we evaluate PEG600-coated ceria nanoparticles (CeNPs) of three sizes (1.2, 4, and 40 nm) for their potential to mitigate NP cell senescence and IVDD in rat model. Among them, the 4 nm-PEG600 CeNPs exhibited the highest therapeutic efficacy, which can be attributed to their low cytotoxicity and improved physiological stability within disc tissue. Mechanistically, CeNPs attenuated IVDD by countering ROS accumulation-induced NP senescence, as supported by assessments of ECM metabolism, senescence-associated secretory phenotype (SASP) expression, cellular senescence and proliferation, and mitochondrial function. Importantly, beyond their direct ROS-scavenging ability, the 4 nm PEG600-CeNPs suppressed cellular senescence through inhibition of AKT Ser473 phosphorylation in the PI3K-AKT pathway. These findings establish size-optimized CeNPs as a promising dual-targeting (antioxidant and anti-senescence) strategy for IVDD treatment.