A DNA Device that Mediates Selective Endosomal Escape and Intracellular Delivery of Drugs and Biologicals

Design of materials to aid intracellular delivery of agents can greatly improve medical treatments. While DNA is a molecule difficult to introduce into cells, DNA can be engineered into devices capable of intracellular delivery. However, transport mediated by DNA devices void of other structural materials, with sizes greater than that associated with non‐specific penetration, and a targeting capacity enough to overcome non‐specific pathways has not yet been achived. This study demonstrates that this is possible. Submicrometer (200 nm) dendrimers built of DNA (nucleodendrimers (NDs)) are coupled to antibodies against selected cell‐surface receptors and compared to polymer nanoparticles (NPs). NDs and NPs bind specifically to cells expressing these targets and efficiently enter cells via the pathway associated with the selected receptor. While NPs traffic to perinuclear endo‐lysosomes, NDs remain scattered throughout the cell, suggesting endosomal escape. This is confirmed in vitro, where NDs disrupt membranous vesicles at endosomal‐like pH and in cell culture, where they provide endosomal escape of model drugs, sugars, proteins, and nucleic acids; allow access to other intracellular compartments; result in measurable effects of cargoes, and; do not cause cytotoxicity. Therefore, these DNA nanodevices can be used to selectively overcome intracellular barriers, underscoring the growing range of applications of DNA materials.