Recently we reported the detection and sizing of the smallest RNA virus MS2 with a mass of 6 ag from the resonance frequency shift of a whispering gallery mode-nanoshell hybrid resonator (WGM-h) upon adsorption on the nanoshell and anticipated that single protein above 0.4 ag should be detectable but with considerably smaller signals. Here, we report the detection of single thyroid cancer marker (Thyroglobulin, Tg) and bovine serum albumin (BSA) proteins with masses of only 1 ag and 0.11 ag (66 kDa), respectively. However, the wavelength shifts are enhanced beyond those anticipated in our earlier work by 240% for Tg and 1500% for BSA. This surprising sensitivity is traced to a short-range reactive field near the surface of our Au nanoshell receptor due to intrinsic random bumps of protein size, leading to an unanticipated increase in sensitivity to single protein, which grows larger as the protein diminishes in size. As a consequence of the largest signal-to-noise ratio in our BSA experiments (S/N ≈ 13), we conservatively estimated a new protein limit of detection for our WGM-h of 5 kDa.

We report the label-free detection and sizing by a microcavity of the smallest individual RNA virus, MS2, with a mass only $1% of InfluenzaA (6 vs. 512 ag). Although detection of such a small bio-nano-particle has been beyond the reach of a bare spherical microcavity, it was accomplished with ease (S/N ¼ 8, Q ¼ 4 Â 10 5) using a single dipole stimulated plasmonic-nanoshell as a microcavity wavelength shift enhancer, providing an enhancement of $70Â, in agreement with theory. Unique wavelength shift statistics are recorded consistent with an ultra-uniform genetically programmed substance that is drawn to the plasmonic hot spots by light-forces. V

The authors present an approach for specific and rapid unlabeled detection of a virus by using a microsphere-based whispering gallery mode sensor that transduces the interaction of a whole virus with an anchored antibody. They show theoretically that this sensor can detect a single virion below the mass of HIV. A micro-fluidic device is presented that enables the discrimination between viruses of similar size and shape.

We report on molecular weight dependence measurements for an optical resonance biosensor. A dielectric microparticle is evanescently coupled with an optical fiber for the resonance stimulation, and a shift of the resonance wavelength is measured to monitor protein monolayer formation on the microparticle surface. Wavelength shifts for proteins over two orders of magnitude in molecular weight are measured. We show that the shift is proportional to molecular weight to the one-third power. Our result demonstrates that the optical resonance biosensor provides protein size information upon detection. This molecular weight dependency differentiates optical resonance sensing from electrical detection using field-effect transistors.

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