A Polymer Physics Perspective on Why PEI Is an Effective Nonviral Gene Delivery Vector

Polyethyleneimine (PEI) was the first polycation shown to have a high transfection efficiency among nonviral gene delivery vectors. The high transfection efficiency was attributed to the proton sponge effect due to the partially protonated amines on PEI chains. Although the proton sponge effect has been debated, here we provide a look at PEI structure and dynamics from a polymer physics perspective. We discuss the protonation equilibrium on PEI chains, the conformational change of PEI chains, and the ion condensation on PEI chains. These three processes can all act favorably for the release of nucleic acids from the endosome and lead to high transfection efficiency. These three processes all stem from the unique chemical structure of PEI, exemplifying how chemical structure determines property.