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.