This study demonstrates a novel approach towards the development of advanced protein assay systems based on physically functionalized, magnetic-core/porous-shell CoFe2O4/SiO2 composite nanoparticles. The preparation, characterization, and measurement of the relevant properties of the protein assay system is discussed, and the system is used for the detection of cancer antigen 15-3 (CA 15-3, used as a model here) in clinical immunoassays. The protein assay system, based on nanometer-sized magnetic cores and silica shells, shows good adsorption properties for the selective attachment of CA 15-3 antibodies specific to CA 15-3. The core/shell nanostructures exhibit good magnetic properties, which enables their integration into a quartz crystal microbalance (QCM) detection cell with the help of a permanent magnet. Under optimal conditions, the resulting immunoassay system presents a good QCM response for the detection of CA 15-3, and allows the detection of CA 15-3 at concentrations as low as 1.5 U mL(-1) (U: units). Importantly, the proposed protein assay system can be extended to the detection of other antigens and biological compounds.