Chemotherapeutic Agent-Loaded Nanoparticles Synergizing with X-ray Irradiation to Regulate Fibroblast-like Synoviocytes for Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder characterized by progressive joint destruction and erosive pathology. Synovitis is considered the hallmark pathological manifestation of RA, often affecting multiple joints throughout the body. Hence, developing strategies for accurate delivery of therapeutics to inflamed joints is crucial to improving drug delivery efficiency. Herein, we rationally constructed a nanosystem that consists of gold nanoparticles serving as both drug carriers and radiosensitizers, fibroblast activation protein inhibitor (FAPI) as a targeting ligand for pathological neovascularization, and β-cyclodextrin (β-CD) as a host matrix for encapsulating BET inhibitor I-BET151. The targeted delivery enabled selective accumulation of I-BET151 at inflamed joints to mitigate immune activation by inhibiting the abnormal proliferation and migration of synovial fibroblasts in collagen-induced arthritis mice. Single-cell profiling dissected this nanosystem effectively suppressing synovial inflammation by eliminating activated B cells and reversing the hypoxia-inducible factor 1-alpha (Hif 1α)-driven profibrotic and migratory program of fibroblast-like synoviocytes. Combined with low-dose radiotherapy, comprehensive transcriptome standardization and cellular remodeling in RA were achieved. Therefore, our strategy holds considerable promise for advancing the management of rheumatoid arthritis and offers a potent therapeutic modality for refractory RA.