Advances in SPRi sensors: Enhancing performance for small-molecule detection

In surface plasmon resonance imaging (SPRi), the quantitative detection of small molecules has always been challenging due to their low molecular weight, weak refractive index (RI) perturbations, and low binding affinity, which cause the resulting signals to approach the system noise level in complex matrices. SPRi, as a label-free, real-time optical detection technique with spatial resolution, provides a unique advantage for monitoring interfacial molecular interactions. However, its practical performance in small molecule analysis is still limited by sensitivity, specificity, and throughput. This review provides a comprehensive and systematic summary of recent advancements in SPRi sensor engineering aimed at overcoming these bottlenecks. The review begins with an analysis of the basic principles of SPR and SPRi, as well as the core challenges in small molecule detection. It then focuses on performance enhancement strategies in three main areas: (i) improving sensitivity through optical system optimization, including advancements in angle, wavelength, intensity, and phase detection, combined with drift compensation and the introduction of hyperspectral/microscopic imaging to enhance the detection of subtle RI changes; (ii) enhancing performance through sensor structure optimization, such as bimetallic films, metal–insulator–metal structures, metasurface designs, and nanomaterial-assisted local field enhancement strategies, which significantly improve signal strength and sensitivity; (iii) improving specificity in small molecule detection through efficient recognition element design, antifouling interface construction, and the synergistic use of multiple recognition units. Meanwhile, the review also explores the application of array-based architectures and microfluidic technologies in high-throughput detection, and analyzes the impact of factors such as response time, regeneration ability, and reproducibility on SPRi stability. Finally, it looks forward to the cross-disciplinary integration of nanomaterials, synthetic biology, microfluidic technology, and data-driven methods, which are expected to drive SPRi technology toward miniaturization, intelligence, and clinical transformation, making it a high-performance platform for small molecule detection.