Plasmonic trimer nanoarrays with probe-trapping sites for SERS detection of urinary copper in Wilson's disease

Cu²⁺ plays a critical role in the onset of Wilson's disease (WD), and precise analysis of Cu²⁺ levels in human metabolites is essential for early clinical diagnosis. However, existing clinical detection such as organ biopsies and mass spectrometry are costly, complex and unsuitable for rapid screening. Surface-enhanced Raman scattering (SERS) offers a rapid, label-free, and noninvasive alternative to conventional assays. Nevertheless, SERS fundamentally depends on highly localized electromagnetic "hot spots", which occupy only a very small fraction of the nanoparticle surface (less than 1%), meaning that only molecules residing within these regions can be effectively enhanced. Herein, we develop a SERS chip based on plasmonic Au@Al₂O₃-Au-Au@Al₂O₃ trimer nanoarrays featuring a molecular "trap" architecture. The central Au trap particle possesses selective chemical affinity that guides probes into plasmonic hotspots, enabling spatial overlap between molecular adsorption sites and plasmonic electromagnetic fields and thereby improving SERS sensitivity and reproducibility. When functionalized with trithiocyanuric acid (TA), the nanoarray enables noninvasive detection of urinary Cu²⁺, exhibiting a concentration-dependent Raman shift and band broadening associated with the multistage TA-Cu²⁺ coordination process. These findings demonstrate that the trap-enhanced nanoarray provides a rapid, ultrasensitive, and clinically accessible platform for early screening of WD and broader applications in metabolite.