Abstract The interaction between mesoporous silica nanoparticles covalently functionalized with different ratios of octreotide, a potent agonist for somatostatin receptors (SSTRs), and a scrambled peptide at a constant total peptide loading and SSTR2 was evaluated as a function of receptor expression. Both an increasing octreotide surface concentration and an increasing receptor expression level led to an increased total ligand–receptor interaction. The highest level of selectivity in terms of differences in sensor response between cells exhibiting a low and a high receptor expression level was observed at intermediate octreotide surface concentrations. However, the kinetics of particle internalization decreased with increasing receptor levels, which led to a decrease in selectivity when judged based on particle uptake as compared to the extent of ligand–receptor interactions. Our results highlight the value of direct evaluation of ligand–receptor interactions in addition to particle uptake analyses for enhancing the mechanistic understanding of nanoparticle behavior in biological systems, enabling rational design of actively targeted nanocarriers.