Nucleodendrimers for endosomal escape

Design of carriers 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. Yet, transport mediated by DNA-devices void of other structural material, with size greater than that associated with non-specific penetration, and with targeting capacity enough to overcome non-specific pathways has not been achieved. This study demonstrates that this is possible. Submicrometer (200-nm) dendrimers built of DNA (nucleodendrimers; NDs) were coupled to antibodies against selected cell-surface receptors and compared to polymer nanoparticles (NPs). NDs and NPs bound specifically to cells expressing these targets and efficiently entered cells via the pathway associated with the selected receptors. While NPs trafficked to perinuclear endo-lysosomes, NDs remained scattered throughout the cell, suggesting endosomal escape. This was confirmed in vitro, where NDs disrupted membranous vesicles at endosomal-like pH and in cell culture, where they: a) provided endosomal escape of model drugs, sugars, proteins, and nucleic acids; b) allowed access to other intracellular compartments; c) resulted in measurable effects of cargoes; and d) did not cause cytotoxicity. These DNA-nanodevices can be used to selectively overcome intracellular barriers.