Disclosed herein are compositions and methods for exosome detection with high sensitivity by using a nano-plasmonic sensor. The nano-plasmonic sensor comprises a plurality of nanoapertures suitable for transmission measurements. The detection sensitivity is on the order of 104-fold higher than western blotting and 102-fold higher than enzyme-linked immunosorbent assay (ELISA). A portable imaging system is also disclosed, enabling rapid and high-throughput detection of exosomes. The nano-plasmonic sensor and imaging system can be useful in diagnostics.