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Mechanobiology

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

AUTHORS

Evans BCBrian C , Fletcher RBR Brock , Kilchrist KVKameron V , Dailing EAEric A , Mukalel AJAlvin J , Colazo JMJuan M , Oliver MMatthew , Cheung-Flynn JJoyce , Brophy CMColleen M , Tierney JWJohn W , Isenberg JSJeffrey S , Hankenson KDKurt D , Ghimire KKedar , Lander CCynthia , Gersbach CACharles A , Duvall CLCraig L . Nature communications. 2019 11 1; 10(1). 5012

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.