An anionic, endosome-escaping polymer to potentiate intracellular delivery of cationic peptides, biomacromolecules, and nanoparticles

Brian C. Evans (), R. Brock Fletcher, Kameron V. Kilchrist, Eric A. Dailing, Alvin J. Mukalel, Juan M. Colazo, Matthew Oliver, Joyce Cheung-Flynn, Colleen M. Brophy, John W. Tierney, Jeffrey S. Isenberg, Kurt D. Hankenson, Kedar Ghimire, Cynthia Lander, Charles A. Gersbach and Craig L. Duvall ()
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Brian C. Evans: Vanderbilt University
R. Brock Fletcher: Vanderbilt University
Kameron V. Kilchrist: Vanderbilt University
Eric A. Dailing: Vanderbilt University
Alvin J. Mukalel: University of Pennsylvania
Juan M. Colazo: Vanderbilt University
Matthew Oliver: Duke University School of Medicine
Joyce Cheung-Flynn: Vanderbilt University Medical Center, D-5237 Medical Center North
Colleen M. Brophy: Vanderbilt University Medical Center, D-5237 Medical Center North
John W. Tierney: Vanderbilt University
Jeffrey S. Isenberg: University of Pittsburgh
Kurt D. Hankenson: University of Michigan Medical School
Kedar Ghimire: University of Pittsburgh School of Medicine
Cynthia Lander: Moerae Matrix Inc.
Charles A. Gersbach: Duke University
Craig L. Duvall: Vanderbilt University

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: Abstract Peptides and biologics provide unique opportunities to modulate intracellular targets not druggable by conventional small molecules. Most peptides and biologics are fused with cationic uptake moieties or formulated into nanoparticles to facilitate delivery, but these systems typically lack potency due to low uptake and/or entrapment and degradation in endolysosomal compartments. Because most delivery reagents comprise cationic lipids or polymers, there is a lack of reagents specifically optimized to deliver cationic cargo. Herein, we demonstrate the utility of the cytocompatible polymer poly(propylacrylic acid) (PPAA) to potentiate intracellular delivery of cationic biomacromolecules and nano-formulations. This approach demonstrates superior efficacy over all marketed peptide delivery reagents and enhances delivery of nucleic acids and gene editing ribonucleoproteins (RNPs) formulated with both commercially-available and our own custom-synthesized cationic polymer delivery reagents. These results demonstrate the broad potential of PPAA to serve as a platform reagent for the intracellular delivery of cationic cargo.

Date: 2019
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DOI: 10.1038/s41467-019-12906-y

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