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Inspired by the decoupling of capture and detection in the enzyme\u2010linked immunosorbent assay (ELISA), we developed a click fluoresce and release (CFR) system, which is a two\u2010step detection platform comprising a capture probe and a detection probe. The capture probe converts the detection of an enzyme biomarker into the detection of tetrazine, which is then specifically recognized by the detection probe through a fluorogenic click reaction. Importantly, this click reaction simultaneously regenerates a molecule of tetrazine, establishing a self\u2010propagating cycle for signal amplification. CFR demonstrates superior detection limits and enhanced ability to discriminate low biomarker levels compared to conventional reaction\u2010based fluorescent probes, as validated by ultrasensitive detection of CD13 in complex biofluids. Notably, with this strategy, we found that plasma CD13 levels are significantly elevated in advanced lung cancer patients compared with early\u2010stage patients and healthy participants. Given its modular design, CFR can be readily adapted for the sensitive detection of various biomarkers by simply replacing the capture probe.<\/jats:p>","DOI":"10.1002\/anie.5574366","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T15:09:21Z","timestamp":1785942561000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An ELISA\u2010Inspired Self\u2010Propagating Click\u2010Fluoresce\u2010and\u2010Release Assay for the Ultrasensitive Detection of CD13 in Lung Cancer Patient Plasma"],"prefix":"10.1002","volume":"65","author":[{"given":"Miao","family":"Liu","sequence":"first","affiliation":[{"name":"College of Pharmaceutical Science Soochow University  Suzhou Jiangsu China"},{"name":"Jiang Su Key Laboratory of Antibody\u2010Targeted Drug Research Jiangsu Hengrui Medicine Co., Ltd.  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