Combinatorial synthesis of redox-responsive cationic polypeptoids for intracellular protein delivery application

Abstract

Biologics play an essential role in treating various indications from cancers to the metabolic diseases, while the current development of new classes of intracellular-acting protein drugs is still hindered because of high molecular mass and overall hydrophilicity of proteins creating extremely poor permeability across cell membrane. Hence, there remains an unmet need to develop safe, potent approaches to augment intracellular protein delivery efficiency. Here, we described a facile multi-component reaction system for generating a small library of redox-responsive cationic polypeptoids with high bio-compatibility. The co-assembly of optimized polymer with protein leads to the formation of compacted nanocomplexes with smaller size and high encapsulation efficiency, thus improving cellular internalization via the macropinocytosis and/or caveolae-mediated endocytosis mainly. After endo-lysosomal escape, the nanocomplexes can be disassociated to efficiently release cargo proteins into the cytosol, owing to the intracellular glutathione (GSH)-triggered rapid cleavage of disulfide bonds in polymers backbone. As a result, we screened a promising platform reagent for efficient cytosolic protein delivery application.