DNA tetrahedral nanostructure and example ligand attachments that may enhance target specificity. A) Schematic showing a DNA tetrahedron with various positions for folate attachment (shown as silver bullets on the vertices). Efficacy of siRNA‐mediated gene silencing of green fluorescent protein (GFP) inside cells can vary vastly by the orientation of the folate molecules—the GFP expression plot shows silencing activity of the DNA tetrahedron designed with set A (1, 2, and 3a), set B (1, 2, and 3b), or set C (1, 2, and 3c). *p < 0.018, **p < 0.019 compared with control (naked GFP siRNA). NS, not significant. Reproduced with permission.77 Copyright 2012, Springer Nature. B) Design format for a DNA tetrahedron labeled with a tumor penetrating peptide on one vertex for enhanced targeting (p‐TDN). Mean fluorescence per cell derived from flow cytometry analysis of p‐TDN internalization into cells in comparison to controls—PBS only, dsDNA, tetrahedron without peptide. Reproduced with permission.25 Copyright 2016, American Chemical Society.