Structural Basis for the Stabilization of DNA Nanostructures in Serum with Metallointercalators

Biomedical applications of DNA nanostructures are severely limited by the instability of DNA in serum due to nuclease activity. The self-assembly of metallointercalators in a DNA tetrahedron significantly enhances both the serum stability and the cellular uptake of the DNA nanostructure. Ancillary ligands and metal ions also significantly influence the stability of these nanoassemblies. Three complexes were synthesized, and the stability of the metallointercalator@DNA tetrahedron assembly in serum decreases in the order [Pt^II-(dppz)(py-4NH₂)₂]²⁺ > [Pt^II-(dppz)(en)]²⁺ > [Eu^III-(dppz)(EDTA-BMA)]⁺, a trend that mirrors the affinity of the metallointercalator for the DNA nanostructure and the increase in the melting point of the assembly upon metallointercalation. [Pt^II-(dppz)(py-4NH₂)₂]²⁺ has hydrophobic 4-aminopyridine as the ancillary ligand that likely interacts with the minor groove of DNA. An efficient metallointercalator with ancillary ligands that can occupy the major groove pockets or minor groove provides greater stabilization of DNA nanostructures in serum necessary for biomedical applications.