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Inspired by natural lasso peptides, we engineer a multifunctional lasso-like peptide (LaP) composed entirely of D-amino acids that uniquely integrates a terminal cysteine anchoring domain, a zwitterionic antifouling segment, and a specific IgG recognition segment into a single topology-constrained architecture. The covalently closed lasso topology sterically restricts protease access to cleavage-sensitive peptide bonds, while the all-D-amino acid backbone is inherently invisible to naturally occurring proteases. Together, these features provide dual physical and stereochemical protection while preserving the conformational freedom of the recognition domain for efficient target binding. Compared with a branched peptide (BrP) of identical sequence, the LaP-modified interface exhibits markedly superior resistance to nonspecific protein adsorption in undiluted serum. Molecular dynamics simulations reveal that the lasso constraint induces a superficial, low-affinity binding pose toward carboxypeptidase Y (CPY), whereas BrP penetrates deeply into the enzyme active pocket. Consequently, the LaP-based biosensor shows negligible signal change after CPY treatment, whereas BrP loses most of its activity. The LaP\/AuNPs\/PANI electrochemical biosensor achieves excellent selectivity and maintains its analytical performance even in complex serum matrices. This work establishes a paradigm for designing topology-constrained, multifunctional peptide interfaces that overcome the longstanding trade-off between biofouling and enzymatic degradation, opening new avenues for high-fidelity electrochemical biosensing in complex biological matrices.<\/jats:p>","DOI":"10.1021\/acs.analchem.6c04069","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T07:02:06Z","timestamp":1787036526000},"page":"25341-25349","source":"Crossref","is-referenced-by-count":0,"title":["A Multifunctional\nLasso-like Peptide-Based Electrochemical\nBiosensor: Overcoming Biofouling and Enzymatic Degradation for High-Fidelity\nImmunoglobulin G Assay"],"prefix":"10.1021","volume":"98","author":[{"given":"Yanlong","family":"Huang","sequence":"first","affiliation":[{"name":"Qilu University of Technology (Shandong Academy of Sciences) , , ,","place":["Jinan, China, 250353"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Pan","sequence":"additional","affiliation":[{"name":"Qilu University of Technology (Shandong Academy of Sciences) , , ,","place":["Jinan, China, 250353"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Xu","sequence":"additional","affiliation":[{"name":"Qilu University of Technology (Shandong Academy of Sciences) , , ,","place":["Jinan, China, 250353"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuohan","family":"Lin","sequence":"additional","affiliation":[{"name":"Qilu University of Technology (Shandong Academy of Sciences) , , ,","place":["Jinan, China, 250353"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nianzu","family":"Liu","sequence":"additional","affiliation":[{"name":"Qilu University of Technology (Shandong Academy of Sciences) , , ,","place":["Jinan, China, 250353"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6926-6152","authenticated-orcid":true,"given":"Yingshu","family":"Guo","sequence":"additional","affiliation":[{"name":"Qilu University of Technology (Shandong Academy of Sciences) , , ,","place":["Jinan, China, 250353"]}],"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":[[2026,8,18]]},"reference":[{"issue":"5","key":"2026090306450721000_cit1","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1038\/s41589-018-0034-3","article-title":"Profiling\nand genetic control of the murine immunoglobulin G glycome","volume":"14","author":"Kris\u030ctic\u0301","year":"2018","journal-title":"Nat. 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