Unveiling the Correlation between Protein, Protein Corona, and Target Signal Loss in SERS Detection

The application of surface-enhanced Raman scattering (SERS) technology is hindered by the protein corona in a protein-rich complex matrix, which is a hot and important issue that needs consideration. However, the impact of the protein corona on SERS detection has not been fully studied. Herein, we selected three proteins, α-lactalbumin (α-La), β-lactoglobulin (β-Lg), and bovine serum albumin (BSA), as models for forming a protein corona, and melamine was employed as the target in SERS detection. The results indicate that three proteins form a protein corona on gold nanoparticles (AuNPs), leading to a significant loss of melamine signals. With increasing protein concentration, the degree of loss increases. The protein corona significantly inhibits target-induced nanoparticle aggregation, increases the distance between neighboring nanoparticles, and reduces the formation of “hot-spot” regions. Moreover, the adsorption capacity of AuNPs for melamine decreases, reducing the number of molecules that can achieve direct chemical enhancement. The Raman signal loss caused by different types of proteins, varies, even at the same molecule number, which is related to the deformability of proteins. This deformability determines the density of the protein corona formed on the surface of the AuNPs. Our results advance the fundamental understanding of the relationship between proteins, protein corona, and target signal loss in SERS detection, offering valuable insights for establishing models to predict Raman signal loss in protein-rich samples.