Nanoplasmonic core-shell nanoraspberry chip for ultrasensitive surface-enhanced Raman scattering detection of SARS-CoV-2: A modular nanobiosensor for respiratory virus diagnostics

The development of robust and ultrasensitive point-of-care diagnostics for viral pathogens, particularly for detecting seasonal respiratory viruses, remains a critical challenge, as traditional biosensing platforms often suffer from signal instability and poor performance in complex biological matrices. Here, we introduce a dual-component surface-enhanced Raman scattering (SERS) immunosensor that overcomes these limitations through a new hotspot engineering strategy. Our platform is centred on a core–shell Au@Ag nanotag fabricated from branched gold nano-raspberries (AuNRBs), which creates abundant plasmonic hotspots. A conformal Ag shell strategically confines the 4-aminothiophenol (4-ATP) reporter within these nanogaps, establishing a unique “gap-confined” Raman reporter architecture that ensures exceptional signal stability and reproducibility. This innovative nanotag is complemented by a second SERS-active component: a specialized capture sensor chip of fluorine-doped tin oxide (FTO) modified with a dense layer of Au nanoparticles (AuNPs). Integrated into a sandwich immunoassay for SARS-CoV-2 S2 spike protein, this dual-enhancement platform achieved a sensitive detection range of 1–500 ng/mL with an ultralow limit of detection of 1.07 pg/mL (15.3 fM) in PBS and 1.30 pg/mL (18.6 fM) in human serum. This rapid assay provided results within just 30 min, highlighting its clinical viability to establish a versatile and reliable SERS system with significant potential for rapid, on-site pathogen diagnostics.