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Current protocols for the analysis of single sEV rely mainly on the advanced techniques and require lengthy isolation procedures, limiting applications in clinical diagnosis. Herein, we developed a one\u2010step procedure for rapid isolation of single sEVs from urine, along with an analytical pipeline for the diagnosis of early bladder cancer (BCa). Single sEVs are isolated by an EV\u2010imprinted gold nanohole (EI\u2010AuNH) array that selectively traps individual sEVs and spatially enhances their Raman spectra. After the invalid spectral data from incomplete or absent sEVs was eliminated using Smart\u2010Filter, a convolutional neural network model identifies the origin of the spectra and generates a digital count matrix for each patient. By integrating the digital count data of both tumor\u2010associated and normal sEVs, our model achieves an accuracy of 97.37% in early diagnosis of BCa. Feature extraction using explainable AI identified nine BCa\u2010related signatures, with noticeable reduction on cholesterol and lipids in BCa\u2010associated sEVs. These signatures could further distinguish BCa from other cancers. Overall, the present non\u2010invasive and highly accurate diagnosis platform may revolutionize clinical disease diagnostics through simplified single sEV isolation and advanced modeling.<\/jats:p>","DOI":"10.1002\/anie.202506744","type":"journal-article","created":{"date-parts":[[2025,5,11]],"date-time":"2025-05-11T22:09:09Z","timestamp":1747001349000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["An All\u2010in\u2010One Nanohole Array for Size\u2010Exclusive Trapping and High\u2010Throughput Digital Counting of Single Extracellular Vesicles for Non\u2010Invasive Cancer Screening"],"prefix":"10.1002","volume":"64","author":[{"given":"Lilin","family":"Yin","sequence":"first","affiliation":[{"name":"Research Center for Analytical Sciences Department of Chemistry College of Sciences Northeastern University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianyao","family":"Han","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Synthetical Automation for Process Industries Northeastern University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fulin","family":"Guo","sequence":"additional","affiliation":[{"name":"Research Center for Analytical Sciences Department of Chemistry College of Sciences Northeastern University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuning","family":"Zou","sequence":"additional","affiliation":[{"name":"The MOE Key Laboratory of Spectrochemical Analysis &amp; Instrumentation the Key Laboratory of Chemical Biology of Fujian Province State Key Laboratory of Physical Chemistry of Solid Surfaces Collaborative Innovation Centre of Chemistry for Energy Materials Department of Chemical Biology College of Chemistry and Chemical Engineering Xiamen University  Xiamen China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingpeng","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Urology Liaoning Cancer Hospital &amp; Institute Cancer Hospital of China Medical University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Wang","sequence":"additional","affiliation":[{"name":"Research Center for Analytical Sciences Department of Chemistry College of Sciences Northeastern University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2374-5342","authenticated-orcid":false,"given":"Chaoyong","family":"Yang","sequence":"additional","affiliation":[{"name":"The MOE Key Laboratory of Spectrochemical Analysis &amp; Instrumentation the Key Laboratory of Chemical Biology of Fujian Province State Key Laboratory of Physical Chemistry of Solid Surfaces Collaborative Innovation Centre of Chemistry for Energy Materials Department of Chemical Biology College of Chemistry and Chemical Engineering Xiamen University  Xiamen China"},{"name":"Institute of Molecular Medicine Department of Gastrointestinal Surgery Clinical Laboratory Renji Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Yang","sequence":"additional","affiliation":[{"name":"Research Center for Analytical Sciences Department of Chemistry College of Sciences Northeastern University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,19]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.125"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.07.009"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-018-0036-9"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-00299-w"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-018-0343-6"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22913-7"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-41285-8"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202207037"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ange.202303121"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-021-00693-y"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-020-01034-x"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-37403-1"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.2c07393"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.1c07075"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0561-9"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.9b09119"},{"key":"e_1_2_8_17_1","author":"Shen W.","year":"2018","journal-title":"Angew. 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