A Size-Determined Growth Rule Enables Well-Preserved Silver–Gold Core–Shell Nanocubes for Reliable Surface-Enhanced Raman Scattering Bioanalysis

The reliable application of surface-enhanced Raman scattering (SERS) in bioanalysis is critically constrained by inherent trade-offs among sensitivity, chemical stability, and signal homogeneity of conventional substrate materials. Although silver–gold core–shell nanocubes (Ag@Au NCs) stand out for their high SERS activity and improved stability, preparing complete and uniform Ag@Au NCs remains challenging due to galvanic replacement-induced Ag core etching. To address this problem, this work reveals three distinct growth modes during Au shell deposition and proposes a size-determined growth rule to guide well-preserved Ag@Au NCs synthesis. We identified that larger Ag nanocubes (Ag NCs) with fewer unpassivated {111} facets preferentially form well-preserved Ag@Au NCs through layer epitaxial growth─an exclusive mode enabling intact ultrathin Au shells without Ag core etching. The resulting Ag@Au NCs exhibit exceptional batch-to-batch consistency and retain the high SERS activity of pristine Ag NCs, while achieving prolonged chemical stability (>180 days). Benefiting from their uniform morphology, these NCs can be assembled into highly ordered two-dimensional substrates with superior signal reproducibility (RSD = 4.96%) and plasmon activity (Raman enhancement factor >10 7 ). By integrating this substrate with a tetrahedral DNA-based detection method, a portable SERS biosensor cartridge was developed for multiplexed miRNA profiling in human plasma. Leveraging the superior performance, this platform demonstrates compelling potential for reliable cervical cancer diagnosis and staging. The modular cartridge design also makes it a versatile platform for diverse biomedical applications.