PROJECT SUMMARY Detection of cancer biomarkers in the blood, known as “liquid biopsy”, can in principle improve the accuracy of measuring nearly invisible “minimal residual disease (MRD)”. Exosomes are cell- excreted extracellular vesicles that contain surface proteins and genetic materials (DNA and RNA) that reflect the characteristics and make-up of the parental cell. Analyzing exosomes would therefore provide direct insight into the state of the cancerous cell. For cancer diagnostics in particular, recent evidences have shown that several micro-RNAs are differentially expressed in CTE. Therefore, unlocking the wealth of information in CTE can potentially cause a paradigm shift. However, current barriers for profiling CTE are the following: (1) all existing technologies require blood withdrawal; (2) involve sophisticated protocols; (3) label-free sizing/counting lacks molecular specificity; (4) provide highly averaged results with high background from normal exosomes, thus leading to poor sensitivity. (5) provide “partial” information: either surface antigen or cargo DNA/RNA, but not both. All of the above has led to a simplistic binary outcome that lacks dynamic range and cannot be used frequently with high sensitivity. We propose a multi-pronged solution on a microfluidic arrayed nanoplasmonic sensor & actuator (MANSA) platform for: (1) streamlined isolation, concentration, and profiling. (2) improve sensitivity by monitoring individual unlabeled exosome binding events with dynamic imaging technology complemented by spectroscopic imaging. (3) improve specificity by profiling both surface antigen and internal D/RNA biomarkers at single exosome level. (4) eliminate blood withdrawal using an integrated needle device. (5) benchmark performance with various sample complexity from cancer cell line extracts to cancer patient blood samples. Our goal is to obtain a high-resolution, digital exosome map with both multiplex surface protein and cargo D/RNA biomarker profiles to facilitate high dynamic range enumeration and boost sensitivity. The proposed technology will become a cost- effective, point-of-care-friendly, translational platform that will address a critical need in early cancer and MRD detection to improve cancer healthcare outcomes. The technology can also be broadly applied to exosome-based diagnostics of non-cancer diseases and basic biomedical research.