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

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.