Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and hyperplasia, which is predominantly driven by abnormal activation of fibroblast-like synoviocytes (RA-FLS). Current therapeutic strategies are frequently plagued by major limitations such as suboptimal efficacy and adverse effects. In the present study, a novel nanotherapeutic system (TSN-FLP) was developed by encapsulating Toosendanin (TSN) into liposomes capable of recognizing fibroblast activation protein-α (FAPα), enabling targeted delivery to RA-FLS. The therapeutic potential and its underlying mechanism of TSN-FLP was systematically investigated. The findings indicated that TSN-FLP notably inhibited the proliferation of RA-FLS by inducing cell cycle arrest at the G2/M phase. This was accompanied by downregulating cyclin-dependent kinase 1 (CDK1), which is involved in the crucial regulatory pathway of cell cycle progression. Furthermore, in vivo studies revealed that TSN-FLP administration effectively alleviated joint swelling, attenuated cartilage and bone erosion, and reduced the secretion of pro-inflammatory cytokines, as evidenced by histopathological analysis, micro-computed tomography (CT) imaging, and enzyme-linked immunosorbent assay (ELISA). Collectively, these preclinical findings provide compelling evidence that TSN-FLP exerts a potent therapeutic effect on RA while maintaining a favorable safety profile. Thus, TSN-FLP represents a promising candidate for the development of novel therapeutic interventions against rheumatoid arthritis.