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While Janus kinase (JAK) inhibitors, such as Tofacitinib (Tofa), have shown clinical efficacy in RA treatment, their broad immunosuppressive effects increase the risk of systemic toxicity. To address this challenge, NOR\u2010Tofa, a Nitric oxide (NO)\u2010responsive JAK inhibitor conjugate, designed for selective activation in inflamed joints are developed. NOR\u2010Tofa incorporates an\n                    <jats:italic>o<\/jats:italic>\n                    \u2010phenylenediamine (\n                    <jats:italic>o\u2010<\/jats:italic>\n                    PD) moiety, allowing for NO\u2010mediated drug release at inflammation sites. Structural characterization confirmed the successful synthesis and NO\u2010responsiveness of NOR\u2010Tofa, which exhibited potent JAK inhibition upon activation. In vitro studies using LPS\u2010stimulated macrophages demonstrated that NOR\u2010Tofa effectively suppressed JAK\u2010STAT signaling and reduced the expression of pro\u2010inflammatory cytokines. In vivo, a collagen\u2010induced arthritis (CIA) mouse model revealed that NOR\u2010Tofa treatment significantly alleviated arthritis symptoms and preserved joint structure, with dose\u2010dependent therapeutic efficacy. Pharmacokinetic analysis indicated that NOR\u2010Tofa minimized systemic exposure to tofacitinib while selectively activating in inflamed joints, thereby reducing off\u2010target effects. Moreover, hematological and acute toxicity assessments confirmed the improved safety profile of NOR\u2010Tofa compared to Tofacitinib. These findings establish NO\u2010responsive drug activation as a promising strategy for RA treatment, offering a more targeted and safer alternative to conventional JAK inhibitors.\n                  <\/jats:p>","DOI":"10.1002\/adhm.202501603","type":"journal-article","created":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T05:31:11Z","timestamp":1761715871000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeted Rheumatoid Arthritis Therapy Using a Smart Nitric Oxide\u2010Responsive JAK Inhibition"],"prefix":"10.1002","volume":"15","author":[{"given":"Yeonju","family":"Boo","sequence":"first","affiliation":[{"name":"Department of Chemistry Pohang University of Science and Technology (POSTECH)  77 Cheongam\u2013Ro, Nam\u2013Gu Pohang Gyeongbuk 37673 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sangmin","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Chemistry Pohang University of Science and Technology (POSTECH)  77 Cheongam\u2013Ro, Nam\u2013Gu Pohang Gyeongbuk 37673 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seohee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Chemistry Pohang University of Science and Technology (POSTECH)  77 Cheongam\u2013Ro, Nam\u2013Gu Pohang Gyeongbuk 37673 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yeong Mi","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Chemistry Pohang University of Science and Technology (POSTECH)  77 Cheongam\u2013Ro, Nam\u2013Gu Pohang Gyeongbuk 37673 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4064-0999","authenticated-orcid":false,"given":"Won Jong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Chemistry Pohang University of Science and Technology (POSTECH)  77 Cheongam\u2013Ro, Nam\u2013Gu Pohang Gyeongbuk 37673 Republic of Korea"},{"name":"OmniaMed Co, Ltd.  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