Abstract
The development and exploration of highly effective drugs for rheumatoid arthritis remains an urgent necessity. However, current disease research models are no longer sufficient to meet the rapid development of high-throughput drug screening. In this study, bacterial cellulose simulating the structure of extracellular matrix was used as a 3D culture platform, and THP-1-derived M1 macrophages, representing the inflammatory component, human umbilical vein endothelial cells (HUVECs), simulating the vascular component, and rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs), embodying the synovial pathology, were co-cultured to simulate the pathological microenvironment in RA synovial tissues, and synovial organoids were constructed. Under three-dimensional (3D) culture conditions, there was a notable upregulation of fatty acid-binding protein 4 (FABP4) in polarized macrophages, and an enhancement of pathological phenotypes in HUVECs and RA-FLSs, mediated through the PI3K/AKT signaling pathway, including cell proliferation, migration, invasion and vascularization. Compared to planar cultures and 2D co-cultures, 3D synovial organoids not only exhibit a broader range of transcriptomic features characteristic of rheumatoid arthritis but also demonstrate increased drug resistance, likely due to the more complex and physiologically relevant cell-cell and cell-matrix interactions present in 3D environments. This model offers a promising path for personalized treatment, accelerating precision medicine in rheumatology.