The efficient intracellular delivery of macromolecular drugs such as proteins poses significant challenges due to their large size and vulnerability to degradation. There has been extensive efforts to develop nanomaterials that can facilitate the intracellular delivery of functional proteins, however, current methods often suffer from low serum tolerance, poor escape from degradative lysosomes, and insufficient delivery of large-size proteins. Here, we report a polymer bearing a novel functional group, phenyl carbamoylated guanidine (Ph-CG), that greatly enhances the delivery efficiency to various types of cells. Due to the substantially lowered pKa, the neutral and hydrophobic Ph-CG offers optimized inter-macromolecular interactions via enhanced hydrogen bonding and hydrophobic interactions. The planarity of the Ph-CG also leads to better intracellular entry of protein complexes. The gradual isolation of the phenyl ring from the carbamoylated guanidine moiety resulted in significant decrease of protein delivery, demonstrating the importance of the rigid connection among the functional group. Intracellularly delivered apoptosis-inducing proteins significantly induce cell viability inhibitions in a serum containing medium, even as compared to commercially available transfection reagents. The newly developed Ph-CG can be introduced to various existing carriers, tackling the issues associated with protein delivery.

Coplanar and rigid phenyl carbamoylated guanidine group enhances intracellular noncovalent protein delivery

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.