Reactive oxygen species-responsive osthole-ceria nanozyme hybrid for redox regulation and chondroprotection in knee osteoarthritis

Knee osteoarthritis (KOA) is a degenerative joint disease driven by excessive reactive oxygen species (ROS) generation, chronic inflammation, and progressive degradation of the extracellular matrix (ECM). Effective modulation of the redox-inflammatory microenvironment at the KOA lesion site remains a research challenge due to the limited bioavailability of natural antioxidants and the insufficient catalytic stability of conventional nanomaterials. In this study, we constructed an osthole-ceria (OST-CeO2) nanocomposite via a polyethylene glycol (PEG)-assisted coordination assembly strategy to achieve synergistic ROS scavenging and chondroprotection. The as-prepared OST-CeO2 nanocomposites exhibited a uniform quasi-spherical morphology, a hydrodynamic size of approximately 150 nm, a mild positive surface charge, excellent colloidal stability, and pH/ROS dual-responsive release behavior. In vitro results demonstrated that OST-CeO2 possesses significant antioxidant capacity, efficiently scavenging diverse free radicals including DPPH·, ABTS+·, superoxide anion, and hydrogen peroxide in a concentration-dependent manner. In an IL-1β-stimulated ATDC5 chondrocyte inflammation model, OST-CeO2 treatment effectively restored cell viability and significantly downregulated the expression of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6). In an H2O2-induced oxidative stress model, OST-CeO2 markedly inhibited intracellular ROS accumulation, restored the activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), while reducing the level of the lipid peroxidation product malondialdehyde (MDA). In a destabilization of the medial meniscus (DMM)-induced KOA mouse model, intra-articular injection of OST-CeO2 effectively alleviated cartilage erosion, reduced Mankin and OARSI histological scores, and improved joint function. Notably, no obvious toxicity was observed in major organs, indicating good in vivo biosafety. In summary, OST-CeO2 integrates ceria-mediated catalytic ROS decomposition with the inherent antioxidant and anti-inflammatory activities of osthole, constructing a dual-functional nano-antioxidant system capable of effectively reshaping the redox imbalance and inflammatory state within the KOA pathological microenvironment. This study presents a promising nanotherapeutic strategy for cartilage protection and provides a theoretical basis for the design and application of hybrid systems based on natural bioactive molecules and nanozymes in the treatment of degenerative joint diseases.