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Highly efficient delivery of functional cargoes by the synergistic effect of GAG binding motifs and cell-penetrating peptides

Dixon, James E.; Osman, Gizem; Morris, Gavin E.; Markides, Hareklea; Rotherham, Michael; Bayoussef, Zahia; El-Haj, Alicia; Denning, Chris; Shakesheff, Kevin M.

Authors

James E. Dixon

Gizem Osman

Gavin E. Morris

Hareklea Markides

Michael Rotherham

Zahia Bayoussef

Alicia El-Haj

Chris Denning

Kevin M. Shakesheff

Abstract

Protein transduction domains (PTDs) are powerful nongenetic tools that allow intracellular delivery of conjugated cargoes to modify cell behavior. Their use in biomedicine has been hampered by inefficient delivery to nuclear and cytoplasmic targets. Here we overcame this deficiency by developing a series of novel fusion proteins that couple a membrane-docking peptide to heparan sulfate glycosaminoglycans (GAGs) with a PTD. We showed that this GET (GAG-binding enhanced transduction) system could deliver enzymes (Cre, neomycin phosphotransferase), transcription factors (NANOG, MYOD), antibodies, native proteins (cytochrome C), magnetic nanoparticles (MNPs), and nucleic acids [plasmid (p)DNA, modified (mod)RNA, and small inhibitory RNA] at efficiencies of up to two orders of magnitude higher than previously reported in cell types considered hard to transduce, such as mouse embryonic stem cells (mESCs), human ESCs (hESCs), and induced pluripotent stem cells (hiPSCs). This technology represents an efficient strategy for controlling cell labeling and directing cell fate or behavior that has broad applicability for basic research, disease modeling, and clinical application.

Journal Article Type Article
Publication Date Jan 5, 2016
Journal Proceedings of the National Academy of Sciences
Electronic ISSN 1091-6490
Publisher National Academy of Sciences
Peer Reviewed Peer Reviewed
Volume 113
Issue 3
Article Number E291-E299
DOI https://doi.org/10.1073/pnas.1518634113
Publisher URL http://www.pnas.org/content/113/3/E291
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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