Abstract Investigating molecular interactions is crucial for advancing biological research and therapeutic discovery. Traditional analytical techniques often face limitations in sensitivity, quantification accuracy, and simplicity. Metasurfaces support resonances that are widely explored both for far-field wavefront shaping and for near-field sensing. Here, we introduce an innovative inverse-designed multilayer metasurface plasmon resonance (IDMM-SPR) sensor that overcomes these challenges. Using a double-objective optimization method, we developed a sensor with unparalleled sensitivity and stability, capable of analyzing ultra-high affinity and low molecular weight interactions. The IDMM-SPR sensor employs a periodic nanocup array with multilayer metallic materials, optimized through a combination of numerical simulations and machine learning. This design leverages collective resonances, including localized surface plasmon resonance (LSPR), Wood’s anomalies, and the Bloch wave surface plasmon polariton (BW-SPP), to enhance sensing performance. The sensor achieves a figure of merit (FoM) of 26.3 and a detection limit (LOD) for C-reactive protein (CRP) as low as 7.3 pM. Its compatibility with microplate absorbance readers and imaging detection makes it highly practical. The IDMM-SPR sensor demonstrates significant potential for high-throughput molecular interaction analysis, drug development, and disease diagnosis, offering a powerful tool for real-time, label-free detection and quantitative analysis of biomolecular interactions.
Yang et al. (Wed,) studied this question.