{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T09:28:26Z","timestamp":1787390906745,"version":"build-2736575974"},"reference-count":32,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"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":["2024YFA0916700"],"award-info":[{"award-number":["2024YFA0916700"]}],"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":["2024YFA0918600"],"award-info":[{"award-number":["2024YFA0918600"]}],"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":["2021YFB3800900"],"award-info":[{"award-number":["2021YFB3800900"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32470995"],"award-info":[{"award-number":["32470995"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["52233007"],"award-info":[{"award-number":["52233007"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22477122"],"award-info":[{"award-number":["22477122"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32270627"],"award-info":[{"award-number":["32270627"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004826","name":"Natural Science Foundation of Beijing Municipality","doi-asserted-by":"publisher","award":["JQ24007"],"award-info":[{"award-number":["JQ24007"]}],"id":[{"id":"10.13039\/501100004826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Synthetic circular mRNA (hereafter referred to as circRNA) reduces susceptibility to exonuclease\u2010mediated degradation by its covalently closed circular structure, enabling prolonged protein expression for therapeutic applications. In this circular format, protein expression from engineered circRNAs is achieved mainly through cap\u2010independent translation initiation, commonly mediated by internal ribosome entry site (IRES) elements whose activity is influenced by RNA structure. Consequently, the coding sequence (CDS) and other elements should be designed with consideration of inter\u2010region base pairing that can shift IRES folding, a constraint not explicitly addressed by existing linear mRNA CDS optimization algorithms. Here, we present\n                    <jats:italic>circ<\/jats:italic>\n                    Design, an algorithm that explicitly incorporates IRES structural deviation into circRNA sequence design while jointly optimizing codon adaptation and thermodynamic stability. In a rabies virus glycoprotein (RABV\u2010G) vaccine model,\n                    <jats:italic>circ<\/jats:italic>\n                    Design\u2010generated circRNAs showed improved stability, translation efficiency, and vaccine immunogenicity compared with benchmark sequences optimized using conventional linear mRNA CDS design strategies, with CR3 achieving a 3.5\u2010fold increase in neutralizing antibody titers. Polysome profiling and targeted IRES\u2010disruption experiments support IRES structural integrity as a critical determinant of circRNA translation performance. Together, these results establish IRES structural preservation as a mechanistic design principle for circRNA engineering and position\n                    <jats:italic>circ<\/jats:italic>\n                    Design as a rational framework for therapeutic circRNA\u00a0development.\n                  <\/jats:p>","DOI":"10.1002\/anie.4782087","type":"journal-article","created":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T09:21:00Z","timestamp":1787390460000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Optimizing Functional\u2010Domain Integrity of Circular Ribonucleic Acid With Improved Vaccine Immunogenicity by\n                    <i>circ<\/i>\n                    Design Algorithm"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0710-3750","authenticated-orcid":false,"given":"Congcong","family":"Xu","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital, International College of Pharmaceutical Innovation Soochow University Suzhou China"},{"name":"College of Pharmaceutical Sciences Soochow University Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Hangzhou Institute of Medicine Chinese Academy of Sciences Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Chemistry Tsinghua University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyun","family":"Wang","sequence":"additional","affiliation":[{"name":"StemiRNA Therapeutics Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengtao","family":"Pu","sequence":"additional","affiliation":[{"name":"Hangzhou Institute of Medicine Chinese Academy of Sciences Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruofan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Chemistry Tsinghua University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changchang","family":"Deng","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, International College of Pharmaceutical Innovation Soochow University Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongqing","family":"Zhai","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuenan","family":"Chen","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Hu","sequence":"additional","affiliation":[{"name":"China Pharmaceutical University Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Zhang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, International College of Pharmaceutical Innovation Soochow University Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuying","family":"Tang","sequence":"additional","affiliation":[{"name":"StemiRNA Therapeutics Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuhe","family":"Wang","sequence":"additional","affiliation":[{"name":"StemiRNA Therapeutics Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinqi","family":"An","sequence":"additional","affiliation":[{"name":"StemiRNA Therapeutics Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Wang","sequence":"additional","affiliation":[{"name":"StemiRNA Therapeutics Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jichuan","family":"Wu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, International College of Pharmaceutical Innovation Soochow University Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotian","family":"Wang","sequence":"additional","affiliation":[{"name":"StemiRNA Therapeutics Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Liu","sequence":"additional","affiliation":[{"name":"Guangzhou Geneseed Biotech. Co., Ltd Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haifan","family":"Shen","sequence":"additional","affiliation":[{"name":"StemiRNA Therapeutics Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6444-7045","authenticated-orcid":false,"given":"Liang","family":"Huang","sequence":"additional","affiliation":[{"name":"School of EECS Oregon State University Corvallis Oregon USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4175-4741","authenticated-orcid":false,"given":"Zhiyuan","family":"Zhong","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, International College of Pharmaceutical Innovation Soochow University Suzhou China"},{"name":"College of Pharmaceutical Sciences Soochow University Suzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8066-1524","authenticated-orcid":false,"given":"Weihong","family":"Tan","sequence":"additional","affiliation":[{"name":"Hangzhou Institute of Medicine Chinese Academy of Sciences Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2583-818X","authenticated-orcid":false,"given":"Dongsheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Chemistry Tsinghua University Beijing China"},{"name":"Department of Chemistry The Hong Kong Polytechnic University Kowloon Hong Kong SAR China"},{"name":"Research Institute for Future Food The Hong Kong Polytechnic University Kowloon Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1146-7848","authenticated-orcid":false,"given":"Liang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Hangzhou Institute of Medicine Chinese Academy of Sciences Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,22]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2023.102372"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44222-024-00259-1"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2022.05.043"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-024-02204-4"},{"issue":"20","key":"e_1_2_7_6_1","article-title":"Circular RNA Vaccine Induces Potent T Cell Responses","volume":"120","author":"Amaya L.","year":"2023","journal-title":"Proceedings of the National Academy of Sciences of the USA"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-025-01344-5"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5c09798"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05096-6"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2025.01.012"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2024.08.020"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.02.017"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-024-01220-3"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/wrna.1685"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2009.03.005"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-022-01393-0"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-3773(19981102)37:20<2754::AID-ANIE2754>3.0.CO;2-3"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.31635\/ccschem.019.20190009"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-026-01233-9"},{"key":"e_1_2_7_20_1","doi-asserted-by":"crossref","unstructured":"B.Mahmud C. M.Horn andW. E.Tapprich \u201cStructure of the 5' Untranslated Region of Enteroviral Genomic RNA \u201dJournal of Virology93 no.23(2019): e01288\u201319.","DOI":"10.1128\/JVI.01288-19"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1908052116"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06127-z"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/15.3.1281"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6c04991"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adn9961"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26926-0"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-025-01073-5"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-025-01098-w"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1168978"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0164-5"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad4939"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2021.07.042"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-024-02393-y"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.4782087","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.4782087","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.4782087","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T09:21:02Z","timestamp":1787390462000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.4782087"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,22]]},"references-count":32,"alternative-id":["10.1002\/anie.4782087"],"URL":"https:\/\/doi.org\/10.1002\/anie.4782087","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,22]]},"assertion":[{"value":"2026-05-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e4782087"}}