Rapid,
yet accurate and sensitive testing has been shown to be
critical in the control of spreading pandemic diseases such as COVID-19.
Current methods which are highly sensitive and can differentiate different
strains are slow and cannot be conveniently applied at the point of
care. Rapid tests, meanwhile, require a high titer and are not sufficiently
sensitive to discriminate between strains. Here, we report a rapid
and facile potentiometric detection method based on nanoscale, three-dimensional
molecular imprints of analytes on a self-assembled monolayer (SAM),
which can deliver analyte-specific detection of both whole virions
and isolated proteins in microliter amounts of bodily fluids within
minutes. The detection substrate with nanoscale inverse surface patterns
of analytes formed by a SAM identifies a target analyte by recognizing
its surface nano- and molecular structures, which can be monitored
by temporal measurement of the change in substrate open-circuit potential.
The sensor unambiguously detected and differentiated H1N1 and H3N2
influenza A virions as well as the spike proteins of severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) and Middle-East respiratory
syndrome (MERS) coronavirus in human saliva with limits of detection
reaching 200 PFU/mL and 100 pg/mL for the viral particles and spike
proteins, respectively. The demonstrated speed and specificity of
detection, combined with a low required sample volume, high sensitivity,
ease of potentiometric measurement, and simple sample collection and
preparation, suggest that the technique can be used as a highly effective
point-of-care diagnostic platform for a fast, accurate, and specific
detection of various viral pathogens and their variants.