Generation of cytotoxic aptamers specifically targeting fibroblast-like synoviocytes by CSCT-SELEX for treatment of rheumatoid arthritis

适体 指数富集配体系统进化 类风湿性关节炎 下调和上调 细胞毒性T细胞 癌症研究 肿瘤坏死因子α 医学 核仁素 关节炎 免疫学 生物 核糖核酸 分子生物学 体外 基因 核心 核仁 精神科 生物化学
作者
Fang Qiu,Duoli Xie,Hongzhen Chen,Zhuqian Wang,Jie Huang,Chunhao Cao,Yiying Liang,Yang Xu,Dongyi He,Xuekun Fu,Aiping Lü,Chao Liang
出处
期刊:Annals of the Rheumatic Diseases [BMJ]
卷期号:: ard-225565 被引量:7
标识
DOI:10.1136/ard-2024-225565
摘要

Objectives Rheumatoid arthritis (RA) is an autoimmune disease characterised by aggressive fibroblast-like synoviocytes (FLSs). Very few RA patients-derived FLSs (RA-FLSs)-specific surface signatures have been identified, and there is currently no approved targeted therapy for RA-FLSs. This study aimed to screen therapeutic aptamers with cell-targeting and cytotoxic properties against RA-FLSs and to uncover the molecular targets and mechanism of action of the screened aptamers. Methods We developed a cell-specific and cytotoxic systematic evolution of ligands by exponential enrichment (CSCT-SELEX) method to screen the therapeutic aptamers without prior knowledge of the surface signatures of RA-FLSs. The molecular targets and mechanisms of action of the screened aptamers were determined by pull-down assays and RNA sequencing. The therapeutic efficacy of the screened aptamers was examined in arthritic mouse models. Results We obtained an aptamer SAPT8 that selectively recognised and killed RA-FLSs. The molecular target of SAPT8 was nucleolin (NCL), a shuttling protein overexpressed on the surface and involved in the tumor-like transformation of RA-FLSs. Mechanistically, SAPT8 interacted with the surface NCL and was internalised to achieve lysosomal degradation of NCL, leading to the upregulation of proapoptotic p53 and downregulation of antiapoptotic B-cell lymphoma 2 (Bcl-2) in RA-FLSs. When administrated systemically to arthritic mice, SAPT8 accumulated in the inflamed FLSs of joints. SAPT8 monotherapy or its combination with tumour necrosis factor (TNF)-targeted biologics was shown to relieve arthritis in mouse models. Conclusions CSCT-SELEX could be a promising strategy for developing cell-targeting and cytotoxic aptamers. SAPT8 aptamer selectively ablates RA-FLSs via modulating NCL-p53/Bcl-2 signalling, representing a potential alternative or complementary therapy for RA.
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