Osthole–ceria nanozyme hybrid with ROS-responsive release for redox homeostasis and cartilage protection in knee osteoarthritis

Knee osteoarthritis (KOA) is a degenerative joint disorder characterized by excessive reactive oxygen species (ROS) accumulation, persistent inflammation, and progressive extracellular matrix (ECM) degradation. However, effective modulation of the pathological redox-inflammatory microenvironment remains challenging due to the poor bioavailability of natural antioxidants and the limited catalytic durability of conventional nanomaterials. In this study, we report a polyethylene glycol (PEG)-assisted coordination assembly strategy to construct an osthole–ceria (OST–CeO 2 ) nanocomposite with synergistic ROS-scavenging and chondroprotective functions. The resulting OST-CeO 2 nanoparticles exhibit a uniform quasi-spherical morphology, a hydrodynamic diameter of 150 nm, a mildly positive surface charge, excellent colloidal stability, and pH/ROS dual-responsive release profiles. In vitro assays confirm that OST-CeO 2 possesses potent concentration-dependent antioxidant activity against diverse radicals including DPPH·, ABTS + ·, and hydrogen peroxide. In IL-1β-stimulated ATDC5 chondrocytes, OST-CeO 2 treatment restores cell viability and significantly suppresses pro-inflammatory cytokines (IL-1β, TNF-α, IL-6). In an H 2 O 2 -induced oxidative stress model, it effectively quenches intracellular ROS, reinstates antioxidant enzyme activities such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and reduces malondialdehyde (MDA) levels. Furthermore, intra-articular injection of OST-CeO 2 in a destabilization of the medial meniscus (DMM)-induced KOA mouse model significantly attenuates cartilage erosion, lowers Mankin and OARSI histological scores, and improves joint function, with no appreciable toxicity to major organs. Collectively, OST-CeO 2 integrates ceria-mediated catalytic ROS elimination with osthole's inherent antioxidant and anti-inflammatory properties, establishing a dual-functional nano-antioxidant platform that reshapes the redox and inflammatory imbalance in the KOA niche. This study presents a promising nanotherapeutic strategy for cartilage preservation and provides a foundation for designing hybrid systems combining natural bioactive compounds with nanozymes against degenerative joint diseases. Download: Download high-res image (294KB) Download: Download full-size image