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Herein, a tight-locking and high-gain Cas12a-driven strand displacement amplification (CSDA) molecular circuit is developed as a versatile socket without preamplification for programmable sensing of nucleic acid and non-nucleic acid analytes. CSDA relies on an RNA\u2013DNA three-strand hairpin (RD-TSH) switch containing a 2-nt mismatch. RD-TSH suppresses nonspecific amplification and unintended Cas12a self-activation to ensure tight locking. Screening the number of mismatched bases in RD-TSH and molecular-level mechanistic analyses reveal a DNA breathing-driven two-step unlocking mechanism. Only complete unlocking triggers autocatalytic CSDA, allowing high-gain amplification. The sequence-independent unlocking of RD-TSH confers high orthogonality to CSDA, enabling target-specific modules to be coupled to the CSDA socket as interchangeable plugs via programmable crRNA guides, thus achieving universal detection of both nucleic and non-nucleic analytes. Using Vibrio parahaemolyticus DNA, thermostable direct hemolysin, and aflatoxin B1 as representative targets, CSDA achieved ultrasensitive detection in complex matrices with sensitivity improvements of over 5 orders of magnitude, 42-fold, and 602-fold, respectively. This plug-and-play architecture establishes CSDA as a broadly adaptable and ultrasensitive CRISPR\/Cas12a sensing socket, providing a general route toward programmable sensing of diverse analyte classes and a promising strategy for more accurate integrated multitarget analytical platforms.<\/jats:p>","DOI":"10.1021\/acs.analchem.6c04985","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T02:01:39Z","timestamp":1786500099000},"page":"24577-24592","source":"Crossref","is-referenced-by-count":1,"title":["Programmable\nVersatile Socket: A Tight-Locking and\nHigh-Gain CRISPR\/Cas12a Molecular Circuit for Ultrasensitive Sensing\nof Diverse Targets"],"prefix":"10.1021","volume":"98","author":[{"given":"Shoujia","family":"Lin","sequence":"first","affiliation":[{"name":"Hainan University , , ,","place":["Haikou, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangbin","family":"Chen","sequence":"additional","affiliation":[{"name":"Hainan Normal University , , ,","place":["Haikou, China, 571158"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyue","family":"Lang","sequence":"additional","affiliation":[{"name":"Hainan University , , ,","place":["Haikou, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bozhi","family":"Lu","sequence":"additional","affiliation":[{"name":"Hainan University , , ,","place":["Haikou, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5795-7450","authenticated-orcid":true,"given":"Yanwei","family":"Jia","sequence":"additional","affiliation":[{"name":"University of Macau , , ,","place":["Macao, China, 999078"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6741-5302","authenticated-orcid":true,"given":"Huangxian","family":"Ju","sequence":"additional","affiliation":[{"name":"Nanjing University , , ,","place":["Nanjing, China, 210023"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7044-5043","authenticated-orcid":true,"given":"Hongmei","family":"Cao","sequence":"additional","affiliation":[{"name":"Hainan University , , ,","place":["Haikou, China, 570228"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"2026083118454941100_cit1","doi-asserted-by":"publisher","DOI":"10.1111\/1541-4337.13392","article-title":"Microbiological\nand Chemical Hazards in Cultured Meat and Methods for Their Detection","volume":"23","author":"Sogore","year":"2024","journal-title":"Compr. 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