The rapid detection of proteins is very important in the early diagnosis of diseases. Gold nanoparticles (AuNPs) can be engineered to bind biomolecules efficiently and differentially. Cross-reactive sensor arrays have high sensitivity for sensing proteins using differential interactions between sensor elements and bioanalytes. A new sensor array was fabricated using surface-charged AuNPs with dyes supramolecularly encapsulated into the AuNP monolayer. The fluorescence of dyes is partially quenched by the AuNPs and can be restored or further quenched due to the differential interactions between AuNPs with proteins. This sensing system enables the discrimination of proteins in both buffer and human serum, providing a potential tool for real-world disease diagnostics.