{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T20:51:32Z","timestamp":1793998292737,"version":"4.8.0"},"reference-count":63,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFA1101200"],"award-info":[{"award-number":["2021YFA1101200"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFA0909400"],"award-info":[{"award-number":["2021YFA0909400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Graves' ophthalmopathy (GO) is an autoimmune disorder marked by orbital inflammation and tissue remodeling, leading to irreversible disfigurement and vision loss. The current first\u2010line glucocorticoid therapy remains palliative, underscoring the critical need for mechanism\u2010based interventions. Autoantibodies against thyrotropin receptor (TSHR) in GO patients highlight its therapeutic potential, yet TSHR inhibitor development faces challenges, including low potency, off\u2010target effects, and mechanistic constraints. To overcome this therapeutic void, YC3, a TSHR\u2010targeting nucleic acid aptamer, has been developed through an innovative approach that combines protein\u2010targeting cell\u2010SELEX with functional selection. YC3 exhibits nanomolar affinity alongside robust pharmacodynamic efficacy. In vitro, YC3 significantly reverses thyroid\u2010stimulating antibodies (TSAbs)\u2010driven hyperactivation in primary human orbital fibroblasts, thereby suppressing pathogenic hallmarks of fibroblasts. In vivo, therapeutic administration of YC3 significantly alleviates ocular symptoms in a GO mouse model. Mechanistic investigations reveal that YC3 binds to a previously unidentified allosteric site within the leucine\u2010rich repeat domain of TSHR, consequently inhibiting receptor activation. Collectively, this study not only identifies YC3 as a promising TSHR\u2010targeting therapeutic candidate but also unveils a novel allosteric site for next\u2010generation inhibitors. These findings highlight the potential of aptamers in both dissecting receptor mechanisms and uncovering cryptic druggable sites, thereby bridging structural biology with targeted drug development.<\/jats:p>","DOI":"10.1002\/advs.202505586","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T08:04:26Z","timestamp":1759824266000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["TSHR\u2010Targeting Nucleic Acid Aptamer Treats Graves' Ophthalmopathy via Novel Allosteric Inhibition"],"prefix":"10.1002","volume":"13","author":[{"given":"Yanchen","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Eye Health Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"},{"name":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health)  Wenzhou Zhejiang 325000 China"},{"name":"Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ende","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"},{"name":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health)  Wenzhou Zhejiang 325000 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weibin","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"},{"name":"Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zeng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"},{"name":"Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neng","family":"Ling","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"},{"name":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health)  Wenzhou Zhejiang 325000 China"},{"name":"Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixing","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuang","family":"Yao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tonghe","family":"Pan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanwen","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yate","family":"Huang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojing","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunhai","family":"Tu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Yan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Eye Health Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianzhang","family":"Wu","sequence":"additional","affiliation":[{"name":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health)  Wenzhou Zhejiang 325000 China"},{"name":"Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mao","family":"Ye","sequence":"additional","affiliation":[{"name":"Molecular Science and Biomedicine Laboratory (MBL) State Key Laboratory of Chemo and Biosensing Hunan Research Center of the Basic Discipline for Cell Signaling College of Biology College of Chemistry and Chemical Engineering Aptamer Engineering Center of Hunan Province Hunan University  Changsha Hunan 410082 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8556-1197","authenticated-orcid":false,"given":"Wencan","family":"Wu","sequence":"additional","affiliation":[{"name":"Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine Vision and Brain Health)  Wenzhou Zhejiang 325000 China"},{"name":"Zhejiang Key Laboratory of Key Technologies for Visual Pathway Reconstruction Eye Hospital Wenzhou Medical University  Wenzhou Zhejiang 325027 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,7]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-024-01016-5"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2013.193"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1510030"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-019-0305-4"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2011.10.005"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023-017-0625-1"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(16)30046-8"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajo.2022.02.015"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00572.2011"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05173-3"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.944715"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.4c01525"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e28397"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-019-01116-4"},{"key":"e_1_2_9_15_1","first-page":"3249","volume":"41","author":"Crisp M.","year":"2000","journal-title":"Investigative Ophthalmology & Visual Science"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2003-031427"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.739994"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1062045"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-021-01652-y"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1210\/edrv.19.6.0352"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2022.0694"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2022.0694"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2011.10.003"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-020-01380-9"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2009.0447"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2010.0123"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-2890"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1136\/bjophthalmol-2015-307399"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2020.0088"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2013-1576"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2021.102666"},{"key":"e_1_2_9_32_1","first-page":"1597","volume":"31","author":"Ryder M.","year":"2021","journal-title":"Thyroid."},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202003563"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr300468w"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2016.01.009"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-51197-w"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2011.0520"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biotechadv.2018.11.001"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2017.00086"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1677\/JME-08-0152"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b10460"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2017.00922"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252111628"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abp8964"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2023.07.054"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aam7928"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S409286"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S446656"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1111\/cen.14681"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2016.199"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1507\/endocrj.EJ22-0391"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2008-0836"},{"key":"e_1_2_9_53_1","first-page":"130","volume":"7","author":"Latif R.","year":"2016","journal-title":"Frontiers In Endocrinology"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c09091"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-010716-104558"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacsau.0c00121"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.2c00073"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa161"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2010.66"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg595"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpz1.770"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-6433-8_13"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.0c00613"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202505586","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.202505586","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202505586","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T11:59:17Z","timestamp":1769687957000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202505586"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,7]]},"references-count":63,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/advs.202505586"],"URL":"https:\/\/doi.org\/10.1002\/advs.202505586","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,7]]},"assertion":[{"value":"2025-03-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e05586"}}