In vivo delivery of transcription factors with multifunctional oligonucleotides.

Abstract

Therapeutics based on transcription factors have the potential to revolutionize medicine but have had limited clinical success due to delivery problems1–4. The delivery of transcription factors is challenging because it requires developing a delivery vehicle that can complex transcription factors, target cells, and stimulate endosomal disruption, with minimal toxicity5,6. In this report we present a novel multifunctional oligonucleotide, termed DARTs (DNA Assembled Recombinant Transcription factors), which can deliver transcription factors with high efficiency in vivo. DARTs are composed of an oligonucleotide that contains a transcription factor binding sequence and hydrophobic membrane disruptive chains that are masked by acid cleavable galactose residues. DARTs have a unique molecular architecture, which allows them to bind transcription factors, trigger endocytosis in hepatocytes, and stimulate endosomal disruption. The DARTs target hepatocytes as a result of the galactose residues and can disrupt endosomes efficiently with minimal toxicity, because unmasking of their hydrophobic domains selectively occurs in the acidic environment of the endosome. We show here that DARTs can deliver the transcription factor Nuclear erythroid 2-related factor 2 (Nrf2) to the liver, catalyze the transcription of Nrf2 downstream genes, and rescue mice from acetaminophen induced liver injury.