Protein-directed fluorescent Au nanoclusters have been widely studied owing to their potential applications in sensing, imaging, and drug and gene delivery. However, the use of nanoclusters in drug delivery is limited by low cellular uptake. In this study, human serum albumin-directed Au nanoclusters served as building blocks to obtain protein nanoparticles by desolvation. The nanoparticles had a decent quantum yield (QY), high colloidal stability and low cytotoxicity, and they could be readily conjugated with biological molecules. The cellular uptake of the Au nanoclusters and nanocluster-loaded protein nanoparticles were studied by confocal fluorescence microscopy. Agglomeration of the protein-directed Au nanoclusters into 50–150-nm nanoparticles dramatically increased the cellular uptake.