Protein Corona Inhibits Endosomal Escape of Functionalized DNA Nanostructures in Living Cells

DNA nanostructures (DNs) can be designed in a EE-DN 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.

Automated summary

DNA nanostructures can be controlled and programmed in a EE-DN manner, and are increasingly used in various biomedical applications such as therapeutic agent delivery. Most nanomaterials become covered by a protein corona when exposed to biological liquids, affecting their cellular uptake and biological response. Studies have shown that cellular uptake of functionalized DNs is linearly dependent on cell size, and the protein corona plays a role in determining the endolysosomal vesicle escape efficiency of DNs coated with an endosome escape peptide.