Xiaonan Wang , Fanfan Guo , Yi Zhang , Ziyi Wang , Jiaqi Wang , Rongrong Luo , Xiao Chu , Yongxing Zhao , Pengchao Sun
{"title":"Dual-targeting inhibition of TNFR1 for alleviating rheumatoid arthritis by a novel composite nucleic acid nanodrug","authors":"Xiaonan Wang , Fanfan Guo , Yi Zhang , Ziyi Wang , Jiaqi Wang , Rongrong Luo , Xiao Chu , Yongxing Zhao , Pengchao Sun","doi":"10.1016/j.ijpx.2023.100162","DOIUrl":null,"url":null,"abstract":"<div><p>Selective suppression of tumor necrosis factor (TNF) α-TNF receptor 1 (TNFR1) signaling is a potent solution for rheumatoid arthritis (RA). Herein, novel composite nucleic acid nanodrugs that simultaneously restrain TNF α binding and TNFR1 multimerization were designed to reinforce inhibition of TNF α-TNFR1 signaling for RA therapy. Towards this end, a novel peptide Pep4‐19 that suppresses TNFR1 clustering was extracted from TNFR1. The resulting peptide and a DNA aptamer Apt2‐55, which inhibits TNF α binding, were integrally or separately anchored on DNA tetrahedron (TD) to obtain nanodrugs with different spatial distribution of Apt2‐55 and Pep4‐19 (TD-3A-3P and TD-3(A-P)). Our results showed that Pep4‐19 enhanced the viability of inflammatory L929 cells. Both TD-3A-3P and TD-3(A-P) suppressed caspase 3, reduced cell apoptosis, and inhibited FLS-RA migration. Compared to TD-3(A-P), TD-3A-3P supplied sufficient flexibility for Apt2‐55 and Pep4‐19, and showed better anti-inflammation properties. Furthermore, TD-3A-3P significantly relieved symptoms in collagen-induced arthritis (CIA) mice, and the anti-RA efficacy through intravenous injection was comparable to transdermal administration <em>via</em> microneedles. Overall, the work provides an effective strategy for RA treatment by dual-targeting TNFR1, and demonstrates that microneedles are promising approach to drug administration in the treatment of RA.</p></div>","PeriodicalId":14280,"journal":{"name":"International Journal of Pharmaceutics: X","volume":null,"pages":null},"PeriodicalIF":5.2000,"publicationDate":"2023-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1f/3d/main.PMC10314200.pdf","citationCount":"1","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Pharmaceutics: X","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2590156723000063","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 1
Abstract
Selective suppression of tumor necrosis factor (TNF) α-TNF receptor 1 (TNFR1) signaling is a potent solution for rheumatoid arthritis (RA). Herein, novel composite nucleic acid nanodrugs that simultaneously restrain TNF α binding and TNFR1 multimerization were designed to reinforce inhibition of TNF α-TNFR1 signaling for RA therapy. Towards this end, a novel peptide Pep4‐19 that suppresses TNFR1 clustering was extracted from TNFR1. The resulting peptide and a DNA aptamer Apt2‐55, which inhibits TNF α binding, were integrally or separately anchored on DNA tetrahedron (TD) to obtain nanodrugs with different spatial distribution of Apt2‐55 and Pep4‐19 (TD-3A-3P and TD-3(A-P)). Our results showed that Pep4‐19 enhanced the viability of inflammatory L929 cells. Both TD-3A-3P and TD-3(A-P) suppressed caspase 3, reduced cell apoptosis, and inhibited FLS-RA migration. Compared to TD-3(A-P), TD-3A-3P supplied sufficient flexibility for Apt2‐55 and Pep4‐19, and showed better anti-inflammation properties. Furthermore, TD-3A-3P significantly relieved symptoms in collagen-induced arthritis (CIA) mice, and the anti-RA efficacy through intravenous injection was comparable to transdermal administration via microneedles. Overall, the work provides an effective strategy for RA treatment by dual-targeting TNFR1, and demonstrates that microneedles are promising approach to drug administration in the treatment of RA.