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

Qiu, Fang1,2; Xie, Duoli1,2; Chen, Hongzhen1; Wang, Zhuqian1,2; Huang, Jie1,2; Cao, Chunhao1,2; Liang, Yiying3; Yang, Xu4; He, Dong-Yi5; Fu, Xuekun1; Lu, Aiping2,6,7; Liang, Chao1,2,8

2024-09-01

10.1136/ard-2024-225565

ANNALS OF THE RHEUMATIC DISEASES   影响因子和分区

0003-4967

1468-2060

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.

Rheumatoid Arthritis Fibroblasts Inflammation Therapeutics Arthritis, Experimental

SCI

英语

第一 ; 通讯

Rheumatology

Rheumatology

WOS:001308753200001

BMJ PUBLISHING GROUP

Web of Science

1.Southern Univ Sci & Technol, Sch Life Sci, Dept Syst Biol, Shenzhen, Peoples R China
2.Hong Kong Baptist Univ, Sch Chinese Med, Inst Integrated Bioinfomed & Translat Sci IBTS, Hong Kong, Peoples R China
3.LingGene Biotech Co Ltd, Shenzhen, Peoples R China
4.St Jude Childrens Res Hosp, Dept Computat Biol, Memphis, TN USA
5.Shanghai Univ Tradit Chinese Med, Shanghai Guanghua Hosp Integrat Med, Dept Rheumatol, Shanghai, Peoples R China
6.Chinese Med & Immune Dis Res, Guangdong Hong Kong Macau Joint Lab, Guangzhou, Peoples R China
7.Shanghai Univ Tradit Chinese Med, Shanghai, Peoples R China
8.Beijing Inst Lifeom, Natl Ctr Prot Sci Beijing, State Key Lab Proteom, Beijing, Peoples R China

Qiu, Fang,Xie, Duoli,Chen, Hongzhen,et al. Generation of cytotoxic aptamers specifically targeting fibroblast-like synoviocytes by CSCT-SELEX for treatment of rheumatoid arthritis[J]. ANNALS OF THE RHEUMATIC DISEASES,2024.

Qiu, Fang.,Xie, Duoli.,Chen, Hongzhen.,Wang, Zhuqian.,Huang, Jie.,...&Liang, Chao.(2024).Generation of cytotoxic aptamers specifically targeting fibroblast-like synoviocytes by CSCT-SELEX for treatment of rheumatoid arthritis.ANNALS OF THE RHEUMATIC DISEASES.

Qiu, Fang,et al."Generation of cytotoxic aptamers specifically targeting fibroblast-like synoviocytes by CSCT-SELEX for treatment of rheumatoid arthritis".ANNALS OF THE RHEUMATIC DISEASES (2024).