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While zwitterionic peptides offer excellent antifouling properties, their typical linear architectures are prone to protease hydrolysis, compromising performance and limiting practical use. To overcome this limitation, we engineered a linear peptide through structural modulation, stabilizing it into a hairpin-shaped conformation by introducing two disulfide-directed bridges, and designated it as the hairpin-shaped antifouling peptide (HAP). This structural modulation maintains its inherent antifouling properties while the conferred conformational constraints significantly enhance its resistance to enzymatic hydrolysis. Based on this HAP, an antifouling electrochemical biosensor was constructed, which effectively resists nonspecific adsorption while maintaining high enzymatic stability, enabling the direct detection of carbohydrate antigen 15-3 (CA15-3) in human serum with a detection limit of 2.64 mU\u00b7mL\u20131. Importantly, the HAP-based biosensor demonstrates reliability on par with commercial enzyme-linked immunosorbent assay methods and successfully discriminates between healthy individuals and cancer patients. With its high accuracy and capacity for direct detection, the platform offers a promising strategy for analyzing cancer biomarkers in serum, potentially enabling more timely and effective clinical diagnosis and treatment.<\/jats:p>","DOI":"10.1021\/acs.analchem.6c02693","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T14:05:17Z","timestamp":1785852317000},"page":"23662-23671","source":"Crossref","is-referenced-by-count":0,"title":["Engineering\na Disulfide-Directed Hairpin-Shaped Antifouling\nPeptide for Reliable Electrochemical Detection of CA15-3 in\nHuman Serum"],"prefix":"10.1021","volume":"98","author":[{"given":"Shuyu","family":"Jiang","sequence":"first","affiliation":[{"name":"Qingdao University of Science and Technology , , ,","place":["Qingdao, China, 266042"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shicheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Qingdao University of Science and Technology , , ,","place":["Qingdao, China, 266042"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Song","sequence":"additional","affiliation":[{"name":"Qingdao University of Science and Technology , , ,","place":["Qingdao, China, 266042"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6075-7089","authenticated-orcid":true,"given":"Xiliang","family":"Luo","sequence":"additional","affiliation":[{"name":"Qingdao University of Science and Technology , , ,","place":["Qingdao, China, 266042"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"2026081809080851500_cit1","doi-asserted-by":"publisher","first-page":"118346","DOI":"10.1016\/j.trac.2025.118346","article-title":"Targeting hepatocellular\ncarcinoma with aptamers: from biomarker detection to therapeutic applications","volume":"191","author":"Casian","year":"2025","journal-title":"TrAC, Trends Anal. 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