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The long waiting time for classic nucleic acid test results highlights the importance of developing alternative rapid biosensing methods. Herein, we propose a fiber-optic biolayer interferometry-based biosensor (FO-BLI) to detect SARS-CoV-2 spike proteins, extracellular domain (ECD), and receptor-binding domain (RBD) in artificial samples in 13 min. The FO-BLI biosensor utilized an antibody pair to capture and detect the spike proteins. The secondary antibody conjugated with horseradish peroxidase (HRP) reacted with the enzyme substrate for signal amplification. Two types of substrates, 3,3\u2032-diaminobenzidine (DAB) and an advanced 3-Amino-9-ethylcarbazole (i.e., AMEC), were applied to evaluate their capabilities in enhancing signals and reaching high sensitivity. After careful comparison, the AMEC-based FO-BLI biosensor showed better assay performance, which detected ECD at a concentration of 32\u2013720 pM and RBD of 12.5\u2013400 pM in artificial saliva and serum, respectively. The limit of detection (LoD) for SARS-CoV-2 ECD and RBD was defined to be 36 pM and 12.5 pM, respectively. Morphology of the metal precipitates generated by the AMEC-HRP reaction in the fiber tips was observed using field emission scanning electron microscopy (SEM). Collectively, the developed FO-BLI biosensor has the potential to rapidly detect SARS-CoV-2 antigens and provide guidance for \u201csample-collect and result-out on-site\u201d mode.<\/jats:p>","DOI":"10.3390\/s22103768","type":"journal-article","created":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T21:36:06Z","timestamp":1652736966000},"page":"3768","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Rapid Optical Biosensing of SARS-CoV-2 Spike Proteins in Artificial Samples"],"prefix":"10.3390","volume":"22","author":[{"given":"Ying","family":"Tao","sequence":"first","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China"},{"name":"CenBRAIN Lab, School of Engineering, Westlake University, Hangzhou 310024, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9470-8143","authenticated-orcid":false,"given":"Sumin","family":"Bian","sequence":"additional","affiliation":[{"name":"CenBRAIN Lab, School of Engineering, Westlake University, Hangzhou 310024, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengbo","family":"Wang","sequence":"additional","affiliation":[{"name":"CenBRAIN Lab, School of Engineering, Westlake University, Hangzhou 310024, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6364-6448","authenticated-orcid":false,"given":"Hongyong","family":"Zhang","sequence":"additional","affiliation":[{"name":"CenBRAIN Lab, School of Engineering, Westlake University, Hangzhou 310024, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2960-441X","authenticated-orcid":false,"given":"Wenwen","family":"Bi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Structural Biology of Zhejiang Province, School of Life Science, Westlake University, Hangzhou 310024, China"},{"name":"Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peixi","family":"Zhu","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4137-7272","authenticated-orcid":false,"given":"Mohamad","family":"Sawan","sequence":"additional","affiliation":[{"name":"CenBRAIN Lab, School of Engineering, Westlake University, Hangzhou 310024, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/s41579-020-00468-6","article-title":"Coronavirus biology and replication: Implications for SARS-CoV-2","volume":"19","author":"Kratzel","year":"2021","journal-title":"Nat. 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