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In this study, we present a click-chemistry-enhanced dynamic light scattering (DLS) immunoassay for the ultrasensitive detection of glial fibrillary acidic protein (GFAP), a clinically significant blood biomarker for brain injury. Unlike conventional DLS immunoassays, which rely on weak antigen\u2013antibody interactions to drive DLS probe aggregation, the proposed approach transforms immunorecognition into a rapid covalent amplification process through click chemistry. A systematic comparison of three click-chemistry-driven aggregation reactions demonstrated that faster association kinetics led to more efficient probe aggregation and stronger signal amplification. On this basis, the optimized inverse electron-demand Diels\u2013Alder reaction (IEDDA)-enhanced DLS immunoassay exhibits the highest sensitivity for GFAP detection, achieving a limit of detection of 210 fg mL\u20131, which is 109-fold and 348-fold lower than that of conventional DLS immunoassays and ELISA methods, respectively. The detection time of the proposed method was only 26 min. Additionally, the IEDDA-enhanced DLS immunoassay exhibits favorable performance in the analysis of clinical serum samples. In conclusion, this study introduces an effective signal amplification strategy utilizing click chemistry to enhance the sensitivity of DLS immunoassays, thereby providing a promising analytical platform for the rapid assessment of TBI.<\/jats:p>","DOI":"10.1021\/acs.analchem.6c03218","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T14:05:28Z","timestamp":1785852328000},"page":"23383-23389","source":"Crossref","is-referenced-by-count":0,"title":["Click-Chemistry-Enhanced\nDynamic Light Scattering\nImmunoassay for Ultrasensitive GFAP Detection in Traumatic Brain Injury"],"prefix":"10.1021","volume":"98","author":[{"given":"Weipeng","family":"Tong","sequence":"first","affiliation":[{"name":"Nanchang University , , ,","place":["Nanchang, P. R. China, 330047"]},{"name":"Nanchang University , , ,","place":["Nanchang, P. R. China, 330047"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Fang","sequence":"additional","affiliation":[{"name":"Nanchang University , , ,","place":["Nanchang, P. R. China, 330006"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjian","family":"Yao","sequence":"additional","affiliation":[{"name":"Nanchang University , , ,","place":["Nanchang, P. R. China, 330047"]},{"name":"Nanchang University , , ,","place":["Nanchang, P. R. China, 330047"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujia","family":"Chen","sequence":"additional","affiliation":[{"name":"Nanchang University , , ,","place":["Nanchang, P. R. China, 330047"]},{"name":"Nanchang University , , ,","place":["Nanchang, P. R. China, 330047"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenghang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Fuzong Clinical Medical College of Fujian Medical University (900th Hospital) , , ,","place":["Fuzhou, P. R. China, 350025"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Cao","sequence":"additional","affiliation":[{"name":"Fuzhou University Affiliated Provincial Hospital , ,","place":["Fuzhou, P. R. China, 350001"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8908-0443","authenticated-orcid":true,"given":"Xiaolin","family":"Huang","sequence":"additional","affiliation":[{"name":"Nanchang University , , ,","place":["Nanchang, P. R. China, 330047"]},{"name":"Nanchang University , , ,","place":["Nanchang, P. R. China, 330047"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5141-0841","authenticated-orcid":true,"given":"Yonghua","family":"Xiong","sequence":"additional","affiliation":[{"name":"Nanchang University , , ,","place":["Nanchang, P. R. China, 330047"]},{"name":"Nanchang University , , ,","place":["Nanchang, P. R. China, 330047"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"issue":"11","key":"2026081809075521000_cit1","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1016\/S1474-4422(22)00309-X","article-title":"Traumatic brain injury: progress and challenges in\nprevention, clinical care, and research","volume":"21","author":"Maas","year":"2022","journal-title":"Lancet\nNeurology"},{"issue":"12","key":"2026081809075521000_cit2","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1016\/S1474-4422(17)30371-X","article-title":"Traumatic brain injury: integrated approaches\nto improve\nprevention, clinical care, and research","volume":"16","author":"Maas","year":"2017","journal-title":"Lancet\nNeurology"},{"issue":"11","key":"2026081809075521000_cit3","doi-asserted-by":"publisher","first-page":"2878","DOI":"10.1007\/s00415-019-09541-4","article-title":"Recent advances in\ntraumatic brain\ninjury","volume":"266","author":"Khellaf","year":"2019","journal-title":"Journal of Neurology"},{"key":"2026081809075521000_cit4","doi-asserted-by":"publisher","first-page":"106001","DOI":"10.1016\/j.ebiom.2025.106001","article-title":"Beyond mild, moderate,\nand severe traumatic brain injury:\nmodelling severity from clinical, neuroimaging, and blood-based indicators","volume":"121","author":"Nelson","year":"2025","journal-title":"eBioMedicine"},{"issue":"5","key":"2026081809075521000_cit5","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1016\/S1474-4422(15)00002-2","article-title":"Diagnosis, prognosis, and clinical management of mild\ntraumatic brain injury","volume":"14","author":"Levin","year":"2015","journal-title":"Lancet Neurology"},{"issue":"4","key":"2026081809075521000_cit6","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/j.nec.2016.05.011","article-title":"Imaging Evaluation of Acute Traumatic\nBrain Injury","volume":"27","author":"Mutch","year":"2016","journal-title":"Neurosurgery Clinics of North\nAmerica"},{"issue":"6","key":"2026081809075521000_cit7","doi-asserted-by":"publisher","first-page":"3556","DOI":"10.1021\/acsbiomaterials.3c00048","article-title":"Nanoporous\nCarbon Immunosensor for Highly Accurate and Sensitive Clinical Detection\nof Glial Fibrillary Acidic Protein in Traumatic Brain Injury, Stroke,\nand Spinal Cord Injury","volume":"9","author":"Khetani","year":"2023","journal-title":"ACS Biomaterials Science\n& Engineering"},{"issue":"4","key":"2026081809075521000_cit8","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/nrneurol.2013.9","article-title":"Biomarkers\nof mild traumatic brain\ninjury in cerebrospinal fluid and blood","volume":"9","author":"Zetterberg","year":"2013","journal-title":"Nature\nReviews Neurology"},{"key":"2026081809075521000_cit9","doi-asserted-by":"publisher","DOI":"10.1016\/j.bas.2023.102735","article-title":"Blood biomarkers for traumatic brain injury: A narrative review of\ncurrent evidence","volume":"4","author":"Hossain","year":"2024","journal-title":"Brain and Spine"},{"issue":"3","key":"2026081809075521000_cit10","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1038\/s41582-021-00616-3","article-title":"Blood GFAP as an emerging\nbiomarker in brain and spinal\ncord disorders","volume":"18","author":"Abdelhak","year":"2022","journal-title":"Nature Reviews Neurology"},{"issue":"10","key":"2026081809075521000_cit11","doi-asserted-by":"publisher","first-page":"953","DOI":"10.1016\/S1474-4422(19)30282-0","article-title":"Association\nbetween plasma GFAP concentrations and MRI abnormalities\nin patients with CT-negative traumatic brain injury in the TRACK-TBI\ncohort: a prospective multicentre study","volume":"18","author":"Yue","year":"2019","journal-title":"Lancet\nNeurology"},{"issue":"5","key":"2026081809075521000_cit12","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1001\/jamaneurol.2016.0039","article-title":"Time Course and Diagnostic Accuracy\nof Glial and Neuronal Blood Biomarkers GFAP and UCH-L1 in a Large\nCohort of Trauma Patients With and Without Mild Traumatic Brain Injury","volume":"73","author":"Papa","year":"2016","journal-title":"JAMA Neurology"},{"issue":"9","key":"2026081809075521000_cit13","doi-asserted-by":"publisher","first-page":"2780","DOI":"10.1021\/ja711298b","article-title":"A One-Step Homogeneous Immunoassay\nfor Cancer Biomarker Detection Using Gold Nanoparticle Probes Coupled\nwith Dynamic Light Scattering","volume":"130","author":"Liu","year":"2008","journal-title":"J. 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Rev."},{"key":"2026081809075521000_cit27","doi-asserted-by":"publisher","DOI":"10.1016\/j.bios.2020.112614","article-title":"Click chemistry as a tool in biosensing\nsystems for\nsensitive copper detection","volume":"169","author":"Tarnowska","year":"2020","journal-title":"Biosens. Bioelectron."},{"key":"2026081809075521000_cit28","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.ab.2017.08.002","article-title":"Designing binding kinetic\nassay on the bio-layer interferometry\n(BLI) biosensor to characterize antibody-antigen interactions","volume":"536","author":"Kamat","year":"2017","journal-title":"Anal. Biochem."},{"issue":"11","key":"2026081809075521000_cit29","doi-asserted-by":"publisher","first-page":"9206","DOI":"10.1021\/acsomega.1c05659","article-title":"Suppressing\nNonspecific\nBinding in Biolayer Interferometry Experiments for Weak Ligand\u2013Analyte\nInteractions","volume":"7","author":"Dubrow","year":"2022","journal-title":"ACS Omega"},{"issue":"1","key":"2026081809075521000_cit30","doi-asserted-by":"publisher","first-page":"21738","DOI":"10.1038\/s41598-020-78895-x","article-title":"Rapid and\nsensitive detection of\nSARS-CoV-2 antibodies by biolayer interferometry","volume":"10","author":"Dzimianski","year":"2020","journal-title":"Sci. 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