Design of a Dual-Detection System for SERRS Cytokine Detection in the NIR Region Simultaneously Matched with Particles and Signal Molecules

Surface-enhanced resonance Raman scattering (SERRS) represents a synergistic combination of surface-enhanced Raman spectroscopy (SERS) and resonance Raman effects, achieving optimal enhancement when the excitation wavelength, nanoparticle, and molecular resonances are precisely matched. Capitalizing on the superior fluorescence suppression of near-infrared (NIR) excitation is useful for biological applications. We designed a high-performance SERRS tag system through triple-parameter optimization: (1) rationally designed AuAg nanocubes (NCs) with exceptional NIR-SERS activity, (2) resonant Raman reporters (IR1061 and IR808), and (3) 785 nm laser excitation. Multiphysics simulations (COMSOL) revealed theoretical enhancement factors up to 10⁷ for AuAg NCs, with experimental SERRS intensities under 785 nm excitation surpassing visible-light performance by at least 1 order of magnitude. This optimized system achieved ultrasensitive detection of clinically relevant cytokines (IL-6 and IL-1β) with detection limits of 1.56 and 6.56 pg/mL, respectively, within 5 min incubation and effectively inhibited antibody-induced nonspecific adsorption in the dual detection, achieving an excellent effect of 15 pg/mL in in actual samples. Therefore, this work not only designed a highly sensitive SERRS biosensor from a principle perspective but also fully utilized the advantages of Raman spectroscopy to truly achieve the dual detection of cytokines, providing a reference for the application of SERRS in clinical detection systems. What is particularly noteworthy is that the combination of AuAg NCs and IR1061 still exhibits excellent detection performance under the 1064 nm excitation light condition, and it is expected to fill the application gap for in vitro diagnostics (IVD) in the NIR-II region.