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However, their use in multiplexed nucleic acid sensing has been hindered by cross-reactivity and overlapping emission spectra. Here we address these limitations by introducing a fluorescence-lifetime-based multiplexed detection strategy using variants of the DNA fluorogenic aptamer\n                  <jats:italic>Lettuce<\/jats:italic>\n                  that exhibits distinct fluorescence lifetimes when complexed with the fluorogen TO1-biotin. To effectively evolve\n                  <jats:italic>Lettuce<\/jats:italic>\n                  for diverse lifetimes, we developed a large-scale screening platform, termed FAP-FLIM-NGS (fluorogenic\n                  <jats:underline>ap<\/jats:underline>\n                  tamer-based fluorescence lifetime imaging\n                  <jats:underline>m<\/jats:underline>\n                  icroscopy on\n                  <jats:underline>n<\/jats:underline>\n                  ext-\n                  <jats:underline>g<\/jats:underline>\n                  eneration\n                  <jats:underline>s<\/jats:underline>\n                  equencing chips), which measures the fluorescence lifetimes of \u223c10\n                  <jats:sup>4<\/jats:sup>\n                  <jats:italic>Lettuce<\/jats:italic>\n                  \/TO1-biotin complexes directly on an Illumina\n                  <jats:italic>MiSeq<\/jats:italic>\n                  flow cell. Using this approach, three variants with markedly different lifetimes were identified: a single mutant (smC14T, 6.0 ns) and two double mutants (dmA5T\/C14T, 5.2 ns, and dmA5T\/T22A, 4.4 ns). To demonstrate the utility of these\n                  <jats:italic>Lettuce<\/jats:italic>\n                  variants in multiplexed detection, a set of split\n                  <jats:italic>Lettuce<\/jats:italic>\n                  probes targeting viral RNA fragments derived from SARS-CoV-2, MERS-CoV, and influenza A were designed and tested. Phasor plot analysis confirmed that these probes can robustly distinguish individual targets as well as mixtures containing any two or all three targets purely based on distinct fluorescence lifetimes of probes, thereby overcoming the challenges of cross-reactivity and spectral overlap. Beyond this proof of concept, our findings establish a generalizable strategy for engineering FAPs with customized photophysical properties, opening new avenues for next-generation diagnostics and molecular sensing technologies.\n                <\/jats:p>","DOI":"10.64898\/2026.04.13.718069","type":"posted-content","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T06:00:13Z","timestamp":1776319213000},"source":"Crossref","is-referenced-by-count":3,"title":["Lifetime-based multiplexed detection of viral RNA using fluorogenic aptamers"],"prefix":"10.64898","author":[{"given":"Yuan-I","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-An","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"He","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naseem","family":"Siraj","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Purdue University, West Lafayette, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emile J.","family":"Batchelder-Schwab","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Purdue University, West Lafayette, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin-Jui","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siem","family":"Yonas","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenglin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anh-Thu","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohyun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengde","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Purdue University, West Lafayette, IN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengyu","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Chih","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA"},{"name":"Texas Materials Institute, University of Texas at Austin, Austin, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041809450807000_2026.04.13.718069v1.1","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/nmeth.3740","article-title":"Multi-target spectrally resolved fluorescence lifetime imaging microscopy","volume":"13","year":"2016","journal-title":"Nature Methods"},{"key":"2026041809450807000_2026.04.13.718069v1.2","doi-asserted-by":"crossref","unstructured":"Scipioni, L. , Rossetta, A. , Tedeschi, G. & Gratton, E. 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