DNA nanostructures (DNs) can be designed in a controlled and programmable manner, and these structures are increasingly used in a variety of biomedical applications, such as the delivery of therapeutic agents. When exposed to biological liquids, most nanomaterials become covered by a protein corona, which in turn modulates their cellular uptake and the biological response they elicit. However, the interplay between living cells and designed DNs are still not well established. Namely, there are very limited studies that assess protein corona impact on DN biological activity. Here, we analyzed the uptake of functionalized DNs in three distinct hepatic cell lines. Our analysis indicates that cellular uptake is linearly dependent on the cell size. Further, we show that the protein corona determines the endolysosomal vesicle escape efficiency of DNs coated with an endosome escape peptide. Our study offers an important basis for future optimization of DNs as delivery systems for various biomedical applications.

Biodesign Center for Molecular Design and Biomimetics Arizona State University Tempe Arizona 85287 United States

Department of Optical and Biophysical Systems Institute of Physics of the Czech Academy of Sciences Prague 18221 Czech Republic

Institute for Clinical and Experimental Medicine Prague 14021 Czech Republic

J Heyrovský Institute of Physical Chemistry of the Czech Academy of Sciences Prague 18223 Czech Republic

School of Molecular Sciences Arizona State University Tempe Arizona 85287 United States

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