A Retention-Monitoring Assay Based on Logic Profiling Nucleic Acid Framework for Accurate Identification of Extracellular Vesicles

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Extracellular vesicles (EVs) hold promise as a new generation of noninvasive cancer diagnostic biomarkers, but the complexity and heterogeneity of clinical samples limit the detection accuracy and clinical applicability. Herein, we propose a retention-monitoring, label-free plasmonic sensing method based on a dual protein logic profiling framework nucleic acid (DP-FNA) molecular device for the specific and sensitive detection of tumor-derived EVs. The DP-FNA comprises two aptamers to determine the relative expression levels of two target proteins on single EVs through a retention-based logical profiling process. This strategy is minimally affected by the concentrations of EVs, providing significantly improved detection accuracy compared with traditional single aptamer-based assays. Using CD63/EpCAM and EpCAM/CD63 aptamer combinations, we achieved 100% accuracy in distinguishing between cancer and noncancer clinical serum samples, as well as between breast cancer and liver cancer clinical serum samples. We envision that this DP-FNA-based retention-monitoring assay will advance the potential of EVs in early cancer diagnosis.