Development of ROS‐Sensitive Sulfasalazine‐Loaded Ferrocene Nanoparticles and Evaluation of Their Antirheumatic Effects in a 3D Synovial Hyperplasia Model

Abstract Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by joint inflammation, synovial hyperplasia, and bone and cartilage destruction, which significantly impairs physical function and quality of life. Disease‐modifying antirheumatic drugs, such as sulfasalazine (SSZ), are crucial for altering the course and progression of RA; however, their clinical use is hampered by poor water solubility and lack of specificity for the reactive oxygen species (ROS)‐rich environment typical of RA. To overcome these challenges, ROS‐sensitive SSZ‐loaded ferrocene nanoparticles are developed. The nanoparticles facilitate enhanced solubility and stability of SSZ and particularly enable precision targeting through the distinctive redox properties of ferrocene. Using a 3D synovial hyperplasia model with fibroblast‐like synoviocytes derive from RA patients and validate at both the protein and gene levels, these nanoparticles significantly reduce lactate dehydrogenase, ROS, and inflammatory cytokine levels. Further validation using a collagen‐induced arthritis model demonstrates therapeutic efficacy and cytokine modulation in vivo. These findings highlight the potential of ferrocene nanoparticles as a novel and effective therapeutic strategy for RA, offering improved drug delivery and reduced systemic toxicity.