biostudies-literatureUnknownZhang DJoint Funds for the Innovation of Science and Technology, Fujian ProvinceScience Fund Program for Excellent Young Scientists of FujianGuiding Projects of Fujian ProvinceNational Natural Science Foundation of ChinaThe presence of a micropapillary (MPP) component is a crucial determinant of surgical strategies for lung adenocarcinoma (LUAD), yet reliable blood biomarkers for predicting MPP⁺ LUAD remain elusive. Here, we integrate 4D label-free quantitative proteomics, a nanomixing-enhanced microfluidic surface-enhanced Raman spectroscopy (SERS) platform, and machine learning to sensitively identify and validate blood protein biomarkers associated with MPP⁺ LUAD. Comparative proteomics reveal 44 differentially expressed proteins (DEPs) between MPP⁺ and MPP⁻ LUADs, with bioinformatics uncovering their roles in MPP⁺ LUAD formation. To enable sensitive, multiplex detection of 4 upregulated DEPs, the nanomixing effect is leveraged to enhance target protein-SERS barcode interactions while minimizing nonspeAdvanced science (Weinheim, Baden-Wurttemberg, Germany)e2501336https://www.ebi.ac.uk/biostudies/studies/S-EPMC12224922biostudies-literatureProteomics-Empowered Microfluidic-SERS Immunoassay for Identifying and Detecting Biomarkers of Micropapillary Lung Adenocarcinoma.PMC122249222021Y92282023Y00532024J0903012074069Zhang DChen YXu HWang JPeng KfalseProteomics-Empowered Microfluidic-SERS Immunoassay for Identifying and Detecting Biomarkers of Micropapillary Lung Adenocarcinoma.The presence of a micropapillary (MPP) component is a crucial determinant of surgical strategies for lung adenocarcinoma (LUAD), yet reliable blood biomarkers for predicting MPP⁺ LUAD remain elusive. Here, we integrate 4D label-free quantitative proteomics, a nanomixing-enhanced microfluidic surface-enhanced Raman spectroscopy (SERS) platform, and machine learning to sensitively identify and validate blood protein biomarkers associated with MPP⁺ LUAD. Comparative proteomics reveal 44 differentially expressed proteins (DEPs) between MPP⁺ and MPP⁻ LUADs, with bioinformatics uncovering their roles in MPP⁺ LUAD formation. To enable sensitive, multiplex detection of 4 upregulated DEPs, the nanomixing effect is leveraged to enhance target protein-SERS barcode interactions while minimizing nonspe2025-01-01T00:00:00Z2025 May2025-07-28T03:03:43.031Z2025-07-28T03:03:43.031ZS-EPMC122249224031816110.1002/advs.202501336