A nanoplasmonic resonator (NPR) comprising a metallic nanodisk with alternating shielding layer(s), having a tagged biomolecule conjugated or tethered to the surface of the nanoplasmonic resonator for highly sensitive measurement of enzymatic activity. NPRs enhance Raman signals in a highly reproducible manner, enabling fast detection of protease and enzyme activity, such as Prostate Specific Antigen (paPSA), in real-time, at picomolar sensitivity levels. Experiments on extracellular fluid (ECF) from paPSA-positive cells demonstrate specific detection in a complex bio-fluid background in real-time single-step detection in very small sample volumes.
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 This work was supported by NSF Nano-scale Science and Engineering Center (DMI-0327077), NSFSST/Collaborative Research Program (DMI-0427679), and NASA Institute for Cell Mimetic Space Exploration (CMISE), under Award No. NCC 2-1364; NHLBI/NIH HL078534 and NCl/NIH R1CA95393-01; DARPA, and UCSF Prostate Cancer SPORE award (NIH Grant P50 CA89520; and P01 CA072006), under Contract no. DE-ACO2-05CH11231 awarded by the U.S. Department of Energy, at the University of California/Lawrence Berkeley National Laboratory.