Ligand geometry dictates cellular and in vivo uptake of 3D DNA nanostructures

Fabrication of nanoscale DNA devices to generate 3D nano-objects with precise control of shape, size, and presentation of ligands has shown tremendous potential for therapeutic applications. The interactions between different topologies of 3D DNA nanostructures and the cell membranes are crucial for designing efficient tools for interfacing DNA devices with biological systems. The practical applications of these DNA nanocages are still limited in cellular and biological systems owing to the limited understanding of interactions of different surface topologies of DNA nanodevices with cell membranes. The correlation between the geometry of DNA nanostructures and their internalization efficiency remains elusive. We investigated the influence of the shape and size of 3D DNA nanostructure on their cellular internalization efficiency. We found that of different geometries designed, one particular geometry, i.e., the tetrahedral shape, is more favoured over other geometries for their cellular uptake in 2D and 3D cell models. This is also replicable for cellular processes like 3D cell invasion assays in 3D spheroid models and passing the epithelial barriers in in-vivo zebrafish model systems. Our work establishes ground rules for the rational designing of DNA nanodevices for their upcoming biological and biomedical applications.