Cartilage-targeting peptide-modified cerium oxide nanoparticles alleviate oxidative stress and cartilage damage in osteoarthritis

Osteoarthritis (OA) is a degenerative joint disease that leads to a substantial decline in the well-being of older individuals. Chondrocyte senescence and the resultant damage to cartilage tissue, induced by elevated levels of reactive oxygen species within the joint cavity, are significant causative factors in OA development. Cerium oxide nanoparticles (CeONPs) present a promising avenue for therapeutic investigation due to their exceptional antioxidant properties. However, the limited effectiveness of drugs in the joint cavity is often attributed to their rapid clearance by synovial fluid. Polyethylene glycol-packed CeONPs (PEG-CeONPs) were synthesized and subsequently modified with the cartilage-targeting peptide WYRGRLGK (WY-PEG-CeO). The antioxidant free radical activity and the mimetic enzyme activity of PEG-CeONPs and WY-PEG-CeO were detected. The impact of WY-PEG-CeO on chondrocytes oxidative stress, cellular senescence, and extracellular matrix degradation was assessed using in vitro assays. The cartilage targeting and protective effects were explored in animal models. WY-PEG-CeO demonstrated significant efficacy in inhibiting oxidative stress, cellular senescence, and extracellular matrix degradation in OA chondrocytes. The underlying mechanism involves the inhibition of the PI3K/AKT and MAPK signaling pathways. Animal models further revealed that WY-PEG-CeO exhibited a prolonged residence time and enhanced penetration efficiency in cartilage tissue, leading to the attenuation of pathological changes in OA. These findings suggest that WY-PEG-CeO exerts therapeutic effects in OA by inhibiting oxidative stress and suppressing the over-activation of PI3K/AKT and MAPK signaling pathways. This investigation served as a fundamental step towards the advancement of CeONPs-based interventions, providing potential strategies for the treatment of OA.