Enhanced Intracellular Protein Activity by Caveolae-Mediated Endocytosis of Conjugated Polymer/Protein Complexes

Abstract

Conjugated polymers (CPs) with rigid hydrophobic backbones and polar side chains are known for their efficient cellular entry using various endocytic pathways. Here, the efficient delivery of ribonuclease A (RNase A) into the cytosol of a model cancer cell using a charge-neutral CP with phenyl carbamoylated guanidine (Ph-CG) group at the end of a short ethylene oxide side chain is described. This unique combination of the hydrophobic backbone and the polar nonionic side chain facilitates efficient protein complex formation and subsequent cellular entry through a non-lysosomal pathway, leading to concentration-dependent cell viability inhibition at a half-maximal effective concentration of 0.07 µg mL⁻¹ (or 5 nm). This work demonstrates the potential of CPs as carriers for intracellular protein delivery and the importance of the end functional group of protein carriers.