Rapid, high-sensitivity detection of biomolecules using dual-comb biosensing: application to the SARS-CoV-2 nucleocapsid protein

Abstract: Rapid, sensitive detection of biomolecules is important for improved testing methods for viruses as well as biomarkers and environmental hormones. For example, testing for SARS-CoV-2 is essential in the fight against the COVID-19 pandemic. Reverse-transcription polymerase chain reaction (RT-PCR) is the current standard for COVID-19 testing; however, it is hampered by the long testing process. Shortening the testing process while achieving high sensitivity would facilitate sooner quarantine and thus presumably prevention of the spread of SARS-CoV-2. Here, we aim to achieve rapid, sensitive detection of the SARS-CoV-2 nucleocapsid protein by enhancing the performance of optical biosensing with a dual-comb configuration of optical frequency combs. The virus-concentration-dependent optical spectrum shift is transformed into a photonic RF shift by frequency conversion between the optical and RF regions, facilitating mature electrical frequency measurements. Furthermore, active-dummy temperature-drift compensation enables very small changes in the virus-concentration-dependent signal to be extracted from the large, variable background signal. This dual-comb biosensing technique has the potential to reduce the COVID-19 testing time to 10 min while maintaining sensitivity close to that of RT-PCR. Furthermore, this system can be applied for sensing of not only viruses but also various biomolecules for clinical diagnosis, health care, and environmental monitoring.