Osteoarthritis (OA) is the most common degenerative joint disease in the world. Gene therapy based on delivering microRNAs (miRNAs) into cells has potential for the treatment of OA. However, the effects of miRNAs are limited by the poor cellular uptake and stability. Here, we first identify a type of microRNA-224-5p (miR-224-5p) from clinical samples of patients with OA that can protect articular cartilage from degeneration and further synthesize urchin-like ceria nanoparticles (NPs) that can load miR-224-5p for enhanced gene therapy of OA. Compared with traditional sphere ceria NPs, the thorns of urchin-like ceria NPs can efficiently promote the transfection of miR-224-5p. In addition, urchin-like ceria NPs have excellent performance of scavenging reactive oxygen species (ROS), which can regulate the microenvironment of OA to further improve the gene treatment of OA. The combination of urchin-like ceria NPs and miR-224-5p not only exhibits favorable curative effect for OA but also provides a promising paradigm for translational medicine.