Chen Yijun, Li Kaiming, Jiao Mengying, Huang Yingshuang, Zhang Zihao, Xue Lingjing, Ju Caoyun, Zhang Can
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China.
Acta Pharm Sin B. 2023 Feb;13(2):787-803. doi: 10.1016/j.apsb.2022.08.012. Epub 2022 Aug 23.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe synovial inflammation 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 TNF-targeting-siRNA (siTNF) as an alternative anti-inflammatory approach for RA treatment. The loaded siTNF act as not only the gene therapeutics to inhibit TNF production by macrophages in inflamed synovium, but also the editors to reprogram neutrophils to anti-inflammatory phenotypes. Leveraging the active tendency of neutrophils to inflammation, the reprogrammed siTNF/neutrophil cytopharmaceuticals (siTNF/TP/NEs) can rapidly migrate to the inflamed synovium, transfer the loaded siTNF to macrophages followed by the significant reduction of TNF expression, and circumvent the pro-inflammatory 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.
类风湿性关节炎（RA）是一种自身免疫性疾病，其特征为严重的滑膜炎症和软骨损伤。尽管RA治疗取得了巨大进展，但仍缺乏能完全治愈RA患者的药物。在此，我们提出一种负载肿瘤坏死因子靶向小干扰RNA（siTNF）的重编程中性粒细胞细胞药物，作为RA治疗的一种替代抗炎方法。负载的siTNF不仅作为基因治疗药物抑制炎症滑膜中巨噬细胞产生肿瘤坏死因子，还作为编辑器将中性粒细胞重编程为抗炎表型。利用中性粒细胞向炎症部位的主动趋化倾向，重编程的siTNF/中性粒细胞细胞药物（siTNF/TP/NEs）可迅速迁移至炎症滑膜，将负载的siTNF传递给巨噬细胞，随后肿瘤坏死因子表达显著降低，并规避中性粒细胞的促炎活性，从而减轻滑膜炎症并改善软骨保护。我们的工作为RA治疗提供了一种有前景的细胞药物，并提出了一个基于活中性粒细胞的基因递送平台。
