Protein coronas formed on engineered particles can alter their targeting ability as they enter biological environments. Here, we engineer polymer-coated silica particles and investigate the influence of protein coronas derived from various sources. The particles were functionalized with a small antibody-mimetic ligand (affibody), and their targeting ability to cancer cells in the presence of protein coronas was determined. Protein coronas derived from human serum showed a dramatic inhibition of specific particle-cell association (from ∼70 to ∼7%), whereas the most abundant protein in human serum – human serum albumin – enhanced the specific association of functionalized particles to SK-OV-3 human ovary cancer cells (to ∼90%). This study shows how protein coronas can both facilitate and impede targeting and provides key insights into the importance of challenging engineered particles with multicomponent biologically relevant environments.