With DNA-based nanomaterials being designed for applicationsincellular environments, the need arises to accurately understand theirsurface interactions toward biological targets. As for any materialexposed to protein-rich cell culture conditions, a protein coronawill establish around DNA nanoparticles, potentially altering thea-priori designed particle function. Here, we first set out to identifythe protein corona around DNA origami nanomaterials, taking into accountthe application of stabilizing block co-polymer coatings (oligolysine-1kPEGor oligolysine-5kPEG) widely used to ensure particle integrity. Byimplementing a label-free methodology, the distinct polymer coatingconditions show unique protein profiles, predominantly defined bydifferences in the molecular weight and isoelectric point of the adsorbedproteins. Interestingly, none of the applied coatings reduced thediversity of the proteins detected within the specific coronae. Wethen biased the protein corona through pre-incubation with selectedproteins and show significant changes in the cell uptake. Our studycontributes to a deeper understanding of the complex interplay betweenDNA nanomaterials, proteins, and cells at the bio-interface.