Abstract Self-assembling nanofibers represent a class of nanomaterials that has been extensively investigated due to their high application versatility, particularly in the fields of drug delivery, cellular targeting, and tumor cell screening. Thanks to the possibility of controlling their chemical, structural, and functional properties, these systems show strong potential in immunotherapy and antigen delivery. Within this framework, the present study aims to analyze the influence of variations in the extent of the hydrophobic surface of nanofibers on the efficiency of cellular internalization processes and on antigen expression in dendritic cells, which are considered key players in the adaptive immune response. The composition of the monomeric unit plays a central role in determining the chemical–geometrical nature of nanofibers and their self-assembly mechanism.