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

Evans BC, Fletcher RB, Kilchrist KV, Dailing EA, Mukalel AJ, Colazo JM, Oliver M, Cheung-Flynn J, Brophy CM, Tierney JW, Isenberg JS, Hankenson KD, Ghimire K, Lander C, Gersbach CA, Duvall CL
Nat Commun. 2019 10 (1): 5012

PMID: 31676764 · PMCID: PMC6825215 · DOI:10.1038/s41467-019-12906-y

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.

MeSH Terms (21)

Acrylates Animals Anions Cations Cell Line Cells, Cultured Drug Delivery Systems Endosomes HEK293 Cells Humans Intracellular Space Macromolecular Substances MCF-7 Cells Mice Nanoparticles NIH 3T3 Cells Peptides Polymers Rats RAW 264.7 Cells Reproducibility of Results

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