Significance With the development of society, the demand for improved quality of human life is increasing. The threats of cancer, pandemic viruses, declining food safety, and environmental pollution have gradually become the critical issues in human society. Therefore, the early diagnosis and treatment of cancer, development of drugs, rapid and sensitive detection of viruses, monitoring of environmental pollution, and inspection of food safety are vital for human life and health. Early biomarkers of cancer, such as tumor necrosis factor (TNF), exosomes, and circulating tumor DNA, have an extremely low abundance in the human body. Environmental pollution and food inspection have also necessitated the requirements for detecting extremely low concentrations of markers. Therefore, biosensors with high specificity and sensitivity are urgently required to satisfy society's needs.Many methods have been used to detect various biochemical markers, including polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), liquid chromatography, and mass spectrometry. The PCR and enzyme-linked immunosorbent assay (ELISA) are the gold standards for nucleic acid and protein detection, respectively. However, the PCR typically requires a long detection time (3 - 3.5 h), expensive instruments and equipment, specific laboratory environments, and professional laboratory personnel. In ELISA, most antibodies require enzyme labeling, which often results in false positives and affects the parameters, making them unsuitable for early detection. Liquid chromatography-mass spectrometry often requires large and expensive mass spectrometers for operation and has low repeatability. However, sensors based on surface plasmon resonance (SPR) do not require expensive markers, and optical detection methods can prevent physical and chemical contact between the sensors and analytes. SPR biosensors can also perform a simple, cost-effective, accurate, and timely detection of biochemical markers to support rapid medical decisions and actions. Currently, the detection limit displayed by SPR sensors is not inferior to that of PCR and ELISA detection methods; the detection program is simpler and can be automated, which compensates for the shortcomings of traditional detection methods and has significant application potential.With the continuous development of the SPR technology for biomarker detection, researchers have significantly expanded thedetection capabilities of SPR sensors. However, traditional SPR sensors are typically susceptible to temperature, have difficulty distinguishing non-specific adsorption, and have difficulty detecting low concentrations and low relative molecular mass analytes. To solve these problems, several research teams have developed methods based on sensor structures and functionalized materials to improve SPR sensor sensitivity. Therefore, a summary of the existing research will guide the future development of this field.Progress In this study, we first divide the detection methods of SPR biosensors into five types based on measurements of different parameters by the sensor. We explain the basic principles of various interrogation methods for detecting biomarkers and present a comparison of the advantages and disadvantages of the different interrogation methods (Table 1). In terms of current research progress, the detection methods for SPR sensors are mainly based on two types: angular interrogation and wavelength interrogation SPR biosensors, which have improved detection accuracy and higher convenience. The phase interrogation and Goos-Hanchen shift interrogation types exhibit higher detection sensitivity and accuracy; however, it is still necessary to continue investigating the optimal structure of chips and instruments. For system complexity, the angular interrogation type and Goos-Hanchen shift interrogation type have simpler structures and broader prospects for portable detection. Next, we summarize the research progress in SPR sensor sensitization from the aspects of nanomaterial sensitization and sensor structure optimization, based on the methods recently used by researchers to enhance SPR sensitivity. In terms of nanomaterials, including precious metal nanoparticles, magnetic nanoparticles, and two-dimensional nanomaterials, the enhancement of detection signals is mainly achieved through large -surface loads or localized surface plasmon resonance (LSPR) coupling to enhance the electric field. The optimization of the sensing structure includes the combination of a SPR sensor with a structure, such as a Fabry-Perot cavity or nanohole array. The Fabry-Perot cavity reduces the signal loss caused by the metal damping effect by binding the light beams in the nanocavity. The nanopore array achieves a simple and sensitive detection based on significant optical transmission. Finally, we summarize the main shortcomings of current SPR sensors and propose possible solutions.Conclusions and Prospects Overall, SPR sensors have the advantages of a low detection limit, wide linear range, low sample requirement, high sensitivity, and high selectivity, with high potential for cancer prevention, virus detection, and environmental pollution monitoring. Researchers can apply appropriate interrogation methods to develop portable, highly sensitive, and high -throughput SPR biosensors. By appropriately selecting and combining various sensitization methods, SPR sensors that can overcome existing detection capabilities are developed. Although SPR sensors still face challenges such as high costs and difficulties in achieving portability, SPR sensor technology will advance with the progress in materials and structural science, maintaining excellent characteristics for biomolecular detection while minimizing costs.
