A Transformable Nanoplatform Precisely Positions Fibroblast‐Like Synoviocytes via FAP‐α for Improved Rheumatoid Arthritis Therapy

Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by joint inflammation, damage, and disability. Activated fibroblast‐like synoviocytes (FLSs), abundant in RA synovium, crucially facilitate disease progression. These activated FLSs drive RA pathogenesis by upregulating adhesion molecules, proinflammatory cytokines, chemokines, and major histocompatibility complex class II (MHC‐II). This upregulation facilitates their interaction with CD4 + T cells, triggering an inflammatory cascade that exacerbates synovial inflammation. To address this, a DSPE‐mPEG 2000 ‐GPA‐KLVFF‐decorated liposome loaded with dexamethasone (DPGK@Lipo‐Dex) is developed to precisely target FLSs in arthritic joints. DPGK@Lipo‐Dex achieves efficient binding to FLSs through a specific enzymatic interaction between fibroblast activation protein‐α (FAP‐α) and GPA, along with prolonged retention in the joints due to the fibrillar transformation of KLVFF. In vitro studies demonstrate that DPGK@Lipo‐Dex enhances cellular uptake and reduces MHC‐II expression on aggressive FLSs. In adjuvant‐induced arthritis (AIA) rats, DPGK@Lipo shows specific distribution patterns that target both inflamed joints and FLSs. Treatment with DPGK@Lipo‐Dex leads to a downregulation of MHC‐II expression, a decrease in the number of activated T cells within the synovium, and a reduction in levels of proinflammatory mediators. Overall, DPGK@Lipo‐Dex effectively suppresses FLSs‐related responses and ultimately results in inflammatory remission. This makes DPGK@Lipo‐Dex a promising candidate for nano‐therapeutic treatment in rheumatoid arthritis.