Rapid, sensitive, on-site identification of SARS-CoV-2 infections is an important tool in the control and management of COVID-19. We have developed a surface-enhanced Raman scattering (SERS) immunoassay for highly sensitive detection of SARS-CoV-2. Single-chain Fv (scFv) recombinant antibody fragments that bind the SARS-CoV-2 spike protein were isolated by biopanning a human scFv library. ScFvs were conjugated to magnetic nanoparticles and SERS nanotags, followed by immunocomplex formation and detection of the SARS-CoV-2 spike protein with a limit of detection of 257 fg/mL in 30 min in viral transport medium. The assay also detected B.1.1.7 (“alpha”), B.1.351 (“beta”), and B.1.617.2 (“delta”) spike proteins, while no cross-reactivity was observed with the common human coronavirus HKU1 spike protein. Inactivated whole SARS-CoV-2 virus was detected at 4.1 × 10⁴ genomes/mL, which was 10–100-fold lower than virus loads typical of infectious individuals. The assay exhibited higher sensitivity for SARS-CoV-2 than commercial lateral flow assays, was compatible with viral transport media and saliva, enabled rapid pivoting to detect new virus variants, and facilitated highly sensitive, point-of-care diagnosis of COVID-19 in clinical and public health settings.

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This perspective provides an overview of the diverse surface-enhanced Raman scattering (SERS)-based sensor platforms that have been developed for in vitro diagnostic applications. To provide focus, protein and nucleic acid detection assays based on the principle of extrinsic SERS sensing are emphasized, as well as their potential for translation to fully integrated point-of-care (POC) test platforms. The development of intrinsic SERS sensors, which are predicated on the direct detection of analytes by laser excitation, entails unique opportunities and challenges deserving of their own attention. As the robust sensing of disease pathogens and cancers in both clinical facilities and limited resource settings is the targeted objective of many next-generation biosensors, the majority of the research progress summarized here centers on SERS sensors developed for the rapid, sensitive and selective detection of disease-causing pathogens and biomarkers. In our effort to communicate a realistic assessment of the progress that has been made and the challenges that lie ahead, we avoid an overtly optimistic appraisal of the current status of SERS diagnostics that does not tacitly acknowledge the difficulties inherent in aligning SERS-based technologies alongside ELISA and PCR technologies as a complementary method for bioanalyte detection possessing unique advantages.