A Cell‐Penetrating Foldamer with a Bioreducible Linkage for Intracellular Delivery of DNA

Despite significant advances in foldamer chemistry, tailored delivery systems based on foldamer architectures, which provide a high level of control over secondary structure, are curiously rare among non-viral technologies for transporting nucleic acids into cells. A potent pH-responsive, bioreducible cell-penetrating foldamer (CPF) was developed through covalent dimerization of a short (8-mer) amphipathic oligourea sequence bearing histidine-type units. This CPF exhibits a high capacity to assemble with pDNA and mediates efficient delivery of nucleic acids into the cell. Furthermore, it does not adversely affect cellular viability and was shown to compare favorably with a cognate peptide transfection agent based on His-rich sequences.