Reprogrammed siTNFa/neutrophil cytopharmaceuticals targeting inflamed joints for rheumatoid arthritis therapy

Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe synovial inflam-mation and cartilage damage. Despite great progress in RA therapy, there still lacks the drugs to completely cure RA patients. Herein, we propose a reprogrammed neutrophil cytopharmaceuticals loading with TNFa-targeting-siRNA (siTNFa) as an alternative anti-inflammatory approach for RA treat-ment. The loaded siTNFa act as not only the gene therapeutics to inhibit TNFa production by macro-pha ges in inflamed synovium, but also the editors to reprogram neutrophils to anti-inflammatory phenotypes. Leveraging the active tendency of neutrophils to inflammation, the reprogrammed siTN-Fa/neutrophil cytopharmaceuticals (siTNFa/TP/NEs) can rapidly migrate to the inflamed synovium, transfer the loaded siTNFa to macrophages followed by the significant reduction of TNFa expression, and circumvent the pro-inflamma tory activity of neutrophils, thus leading to the alleviated synovial inflammation and improved cartilage protection. Our work provides a promising cytopharmaceutical for RA treatment, and puts forward a living neutrophil-based gene delivery platform. (c) 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.