Nucleic acid-mediated SERS Biosensors: Signal enhancement strategies and applications

Surface Enhanced Raman Spectroscopy (SERS) is a powerful spectroscopic analysis technique applied in various fields due to its high selectivity, ultra-high sensitivity, and non-destructiveness. As natural biological macromolecules, nucleic acids perform a significant role in SERS biosensing. In this review, we first summarize how nucleic acids mediate the signal enhancement of SERS biosensors from three aspects: substrate self-assembly, analyte biorecognition, and molecular amplification. Among them, SERS substrates can be self-assembled by both DNA modification and coordination or electrostatic interactions. In the field of biorecognition, analyte biorecognition based on three nucleic acid recognition elements can enhance SERS signals by regulating the distance of analytes or Raman reporter molecules to the SERS substrate. In addition, nucleic acid-based enzyme and enzyme-free amplification can enhance SERS signals by enlarging the quantity of analytes or its nucleic acid intermediates. Subsequently, multidimensional applications of nucleic acid-mediated SERS signal enhancement in biomedicine, food safety, and environmental monitoring are listed. Finally, the current challenges and future exploration of nucleic acid-mediated SERS signal enhancement are discussed.