SERS Biosensors

With about 45 years of history now in its book, SERS has quickly evolved from an excursion from electrochemistry to today’s multidisciplinary, multi-dimensional, and truly multifaceted research field, spanning from the physics of nanoplasmonics to molecular self-assembly and interface engineering in chemistry, from cellular imaging and apoptosis monitoring in biology to as far as virology and zoonotics. Among them, SERS applications in the biomedical and clinical settings might be one of the most significant and impactful contributions. Up until today, commercially or clinically approved biomedical SERS kits or related nanoparticles have unfortunately still been nonexistent, at least partially attributable to several limitations of current SERS biosensors: (1) sensitivity & specificity; (2) quantitative measurements; (3) stability and biocompatibility; and (4) affordability and flexibility. Therefore, there is still quite a long way to go before SERS gets its first FDA-approved diagnostic kit. More than 20 years after first reports of single-molecule SERS observations73, 74 and more than 14 years after first firmly established proof for single-molecule SERS with the bianalyte technique,75 it still remains a great challenge to achieve high sensitivity for SERS detection of biomolecules.76 Molecular specificity in SERS can be managed via host–guest chemistry, antibody–antigen recognition, base–pair hybridization, as well as aptamer–target interactions, among many. However, due to potential non-specific adsorption of biomolecules onto SERS substrates, reducing false positives and ensuring molecular specificity are essential for SERS biosensors.77 Quantitation with SERS used to be a major obstacle, but in recent years several solutions were proposed to address this issue: (1) incorporating internal standards;78 (2) highly uniform SERS nanoparticles such as intra-nanogap particles;79 and (3) multisite sensing.80 While stability and biocompatibility are key properties that the SERS biosensor has to excel in, were it to someday be applied in clinical settings, its affordability and flexibility will to an extent determine the market and the utility of these biosensors. With all the recent advances in SERS biosensing and disease diagnostics, it is noteworthy that the selected literature discussed here partially represents, though not exclusively, a concerted effort within the SERS community to meet some of the most difficult challenges in the design of SERS biosensors via the following: (1) interface design, including hybrid structures of noble metals with thin metal oxide shells (SiO2, TiO2, etc.),81, 82 2D materials (graphene, MoS2, etc.),83–85 MOF,86, 87 mixed SAMs,88 and functional SAMs,89 in order to achieve better substrate stability and analyte attraction capability; (2) integrating SERS modules into other sensing platforms, such as microfluidics,90 electrochemistry,91 physiology,92 super-resolution imaging,93, 94 liquid/gas chromatography, 95 capillary electrophoresis,96 and mass spectrometry,97 for multifunctional biosensing platforms that may allow further downstream operations; and (3) application of machine learning in streamlined processing of large SERS datasets obtained in complex biological environments and extracting biological signatures or patterns useful for early-disease diagnostics. We anticipate that commercialization of SERS biosensors for clinical settings will eventually become a reality as the platform gradually matures in the aforementioned aspects for liquid biopsy or 3D single-cell analysis.