A Theranostic Nanozyme for Osteoarthritis Treatment and Glycosaminoglycan-Targeted Diagnosis of Cartilage Pathology

Abstract The lack of vascular and neural innervations in cartilage often results in poor drug delivery and penetration, compromising the efficacy of current therapeutics. To tackle this clinical challenge, we designed positively charged manganese-doped CeO2 nanozymes that combine reactive oxygen species (ROS)-scavenging activity with prolonged retention in the joint cavity by taking advantage of the negatively charged cartilage matrix. Integrating coarse-grained molecular dynamics simulations with experimental validation, we identified chondroitin sulfate as the key glycosaminoglycan responsible for mediating the retention of these positively charged nanozymes in the joint cavity. After intra-articular administration, manganese-doped CeO2 promoted cartilage defect repair and subchondral bone remodeling in a rat model within 4 weeks. In addition, benefiting from the multiple enzyme mimicking activity of nanozymes, the peroxidase-like activity of manganese-doped CeO2 was explored to develop a pathological assay to detect the state of cartilage repair. This study establishes an integrated framework combining theoretical modeling with experimental validation to elucidate intra-articular retention mechanisms. The framework enables the rational design of theranostic nanozymes that exploit disease-specific pathological features for both diagnosis and therapy.