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The disease process is characterized by the activation of macrophages, which then release tumor necrosis factor-\u03b1 (TNF-\u03b1) and interleukin-1\u03b2 (IL-1\u03b2), accelerating tissue damage. Tackling tissue damage is a crucial target in the treatment of RA. In this study, a macrophage-targeted and pH-response DNA tetrahedron\/methotrexate drug delivery system was constructed by loading methotrexate (MTX) onto a DNA duplex. MTX was used as a drug model, and a pH-response DNA tetrahedron (TET) was used as the drug carrier, which was modified with hyaluronic acid (HA) to target macrophages. The aim of this study was to evaluate the potential of TET as an effective drug carrier for the treatment of RA. On this basis, we successfully prepared TETs loaded with MTX, and in vitro assays showed that the MTX-TET treatment could successfully target macrophages and induce macrophages to polarize to M1 phenotype. At the same time, we also injected MTX-TET intravenously into collagen-induced arthritis (CIA) model mice, and the redness and swelling of the paws of mice were significantly alleviated, proving that the MTX-TET could successfully target inflamed joints and release MTX to treat joint swelling. In addition, the histochemical results showed that the MTX-TET could reduce synovitis and joint swelling in CIA mice, reduce the level of inflammatory factors in vivo, and improve the disease status while maintaining a good biosafety profile. This study showed that the MTX-TET treatment has beneficial therapeutic effects on RA, providing a new strategy for the clinical treatment of RA.<\/jats:p>","DOI":"10.3390\/jfb14110541","type":"journal-article","created":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T10:59:54Z","timestamp":1699009194000},"page":"541","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["A pH-Responsive DNA Tetrahedron\/Methotrexate Drug Delivery System Used for Rheumatoid Arthritis Treatment"],"prefix":"10.3390","volume":"14","author":[{"given":"Yi","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226000, China"},{"name":"Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyu","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Yancheng Third People\u2019s Hospital, Yancheng 224000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinjin","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidong","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Hand Surgery, Affiliated Hospital of Nantong University, Nantong 226000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Li","sequence":"additional","affiliation":[{"name":"Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifeng","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Hand Surgery, Affiliated Hospital of Nantong University, Nantong 226000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1097\/BOR.0000000000000664","article-title":"Evolving concepts of the pathogenesis of rheumatoid arthritis with focus on the early and late stages","volume":"32","author":"Coutant","year":"2020","journal-title":"Curr. 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