{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T08:51:23Z","timestamp":1791622283579,"version":"4.3.4"},"reference-count":51,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:00:00Z","timestamp":1791590400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:00:00Z","timestamp":1791590400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001381","name":"National Research Foundation Singapore","doi-asserted-by":"publisher","award":["NRF\u2010NRFI07\u20102021\u20100005"],"award-info":[{"award-number":["NRF\u2010NRFI07\u20102021\u20100005"]}],"id":[{"id":"10.13039\/501100001381","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                    Bioorthogonality\u2010activatable optical imaging activates caged or quenched probes via bioorthogonal reactions for disease diagnosis. Although chemiluminescence enables low\u2010background detection, it has rarely been applied to bioorthogonality\u2010activatable imaging. Here, we synthesize chemiluminescent tetrazine probes (CLTZs) by coupling a tetrazine acceptor to a phenoxy\u20101,2\u2010dioxetane donor through \u03c0\u2010conjugated vinylene linkers, enabling biomarker and bioorthogonality dual\u2010locked activation for cancer urine testing. Unlike conventional chemiluminophores, tetrazine in CLTZs mediates an internal\u2010conversion\u2010to\u2010a\u2010dark\u2010state quenching mechanism, suppressing chemiluminescence even after phenolate formation. Strong chemiluminescence is restored only when the phenolate form undergoes bioorthogonal reaction with bicyclononyne (BCN), generating pyridazine\u2010containing donor\u2013\u03c0\u2013acceptor chemiluminophores. This unique dark state enables development of an H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    and bioorthogonality dual\u2010locked probe (\n                    <jats:sup>H<\/jats:sup>\n                    BCP), emitting only when both H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    and BCN are present. By engineering BCN into a cancer\u2010activatable bioorthogonal urinary reporter (\n                    <jats:sup>C<\/jats:sup>\n                    BUR) that releases renal\u2010clearable BCN in tumors, a chemiluminescent bioorthogonal pair (\n                    <jats:sup>H<\/jats:sup>\n                    BCP &amp;\n                    <jats:sup>C<\/jats:sup>\n                    BUR) is created. This pair achieves in vivo tumor imaging with a signal\u2010to\u2010background ratio of 438 and detects lung metastasis in early urinary assays with up to 23.9\u2010fold signal enhancement over healthy mice. This work provides a molecular design for bioorthogonality\u2010activatable chemiluminescence toward noninvasive, sensitive disease diagnosis.\n                  <\/jats:p>","DOI":"10.1002\/anie.6875075","type":"journal-article","created":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T08:42:11Z","timestamp":1791621731000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biomarker and Bioorthogonality Dual\u2010Locked Chemiluminescent Probes for Cancer Urine Test"],"prefix":"10.1002","author":[{"given":"Youshi","family":"Lin","sequence":"first","affiliation":[{"name":"School of Chemistry, Chemical Engineering and Biotechnology Nanyang Technological University  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Yuan","sequence":"additional","affiliation":[{"name":"School of Chemistry, Chemical Engineering and Biotechnology Nanyang Technological University  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2553-2068","authenticated-orcid":false,"given":"Xiaogang","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Chemistry, Chemical Engineering and Biotechnology Nanyang Technological University  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8064-6009","authenticated-orcid":false,"given":"Kanyi","family":"Pu","sequence":"additional","affiliation":[{"name":"School of Chemistry, Chemical Engineering and Biotechnology Nanyang Technological University  Singapore Singapore"},{"name":"Lee Kong Chian School of Medicine Nanyang Technological University  Singapore Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,10]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43586\u2010021\u201000028\u2010z"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature0279"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707090104"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200903233"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.981"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.7b00090"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200705805"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.5c00825"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201305969"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja029013y"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201301100"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201031136\u20103"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b02168"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41557\u2010022\u201000963\u20108"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202315425"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201610491"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.1920"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.1250"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt540"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.5c20309"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmaterialslett.9b00281"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c07286"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202314084"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41551\u2010024\u201001340\u20101"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44222\u2010023\u201000074\u20100"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202501681"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0040\u20104039(00)95314\u20100"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.6b09173"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201709347"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201813032"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/ange.202203235"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/ange.202303982"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/ange.202319780"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202310605"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41551\u2010025\u201001588\u20101"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1039\/c4sc03516j"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201802143"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.7b08446"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b02580"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202005429"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202013531"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2021.116400"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202523648"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202417924"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1039\/d3sc02386a"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1039\/c8sc04780d"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2QM01264B"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1039\/D4SC07018F"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44222\u2010024\u201000153\u2010w"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc4027"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2016.02.017"}],"container-title":["Angewandte Chemie International Edition"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.6875075","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/anie.6875075","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/anie.6875075","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T08:42:12Z","timestamp":1791621732000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/anie.6875075"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,10]]},"references-count":51,"alternative-id":["10.1002\/anie.6875075"],"URL":"https:\/\/doi.org\/10.1002\/anie.6875075","archive":["Portico"],"relation":{},"ISSN":["1433-7851","1521-3773"],"issn-type":[{"value":"1433-7851","type":"print"},{"value":"1521-3773","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,10]]},"assertion":[{"value":"2026-07-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-29","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e6875075"}}