Fluorocarbon‐DNA Conjugates for Enhanced Cellular Delivery: Formation of a Densely Packed DNA Nano‐Assembly

Forming nano‐assemblies is essential for delivering DNA conjugates into cells, with the DNA density in the nano‐assembly playing an important role in determining the uptake efficiency. In this study, we developed a strategy for the facile synthesis of DNA strands bearing perfluoroalkyl (RF) groups (RF‐DNA conjugates) and investigated how they affect cellular uptake. An RF‐DNA conjugate bearing a long RF group at the DNA terminus forms a nano‐assembly with a high DNA density, which results in greatly enhanced cellular uptake. The uptake mechanism is mediated by clathrin‐dependent endocytosis. The use of RF groups to densely assemble negatively charged DNA is a useful strategy for designing drug delivery carriers. DNA conjugates were synthesized possessing perfluoroalkyl (RF) groups with different length, position, number, and stereochemistry. Systematical structural investigation revealed that the incorporation of a few long RF groups at the terminus of a DNA strand contributed to the formation of a nano‐assembly with exceedingly high DNA density, which allowed itself taken up into cells efficiently.