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 infectious pathogens as well as biomarkers and pollutants. For example, testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential in the fight against the coronavirus disease 2019 (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. Simplifying and shortening the testing process while achieving its high sensitivity would facilitate sooner quarantine and thus presumably prevent the spread of SARS-CoV-2. Here, we aim to achieve the rapid and sensitive detection of SARS-CoV-2 by enhancing the performance of optical biosensing. We demonstrate optical biosensing based on a dual configuration of optical frequency combs (OFCs), enabling detection of the SARS-CoV-2 nucleocapsid protein. The virus-concentration-dependent optical spectrum shift produced by antigen-antibody interactions is transformed into a photonic radio-frequency (RF) shift by a frequency conversion between the optical and RF regions in the OFC, facilitating rapid and sensitive detection with mature electrical frequency measurements. Furthermore, active-dummy temperature-drift compensation with a dual-comb configuration enables the very small change in the virus-concentration-dependent signal to be extracted from the large, variable background signal caused by temperature disturbance. This dual-comb biosensing technique has the potential to reduce COVID-19 testing time to 10 min, which is considerably shorter than RT-PCR, 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 medical care, food inspection, and environmental monitoring.