DNA Nanostructure-Programmed Cell Entry via Corner Angle-Mediated Molecular Interaction with Membrane Receptors.

Despite its polyanionic nature, DNA can cross the negatively charged membrane to enter living cells by assembling into specific nanostructures, establishing various opportunities for biomedical applications. Mechanistic studies to explain how the geometrical parameters of DNA nanostructures impact the cell entry are critical but elusive. Here, we use experimentation and simulation to study the interaction between cells and three typical framework nucleic acids (FNAs), including tetrahedron, triangular prism, and cube. Different cellular uptake efficiency was observed among these FNAs, and similar distinction consistently existed in multiple cell lines. Scavenger receptors (SRs) were demonstrated to be essential in mediating the uptake process. Molecular docking simulations revealed that the SR binding predominantly depended on the corner angle of FNAs, determining cellular internalization frequency. This study clearly explains how FNAs interact with the membrane to initiate cell entry, offering new clues for the design of theranostic nanocarriers and the study of virus invasion.