Phosphocholine-Functionalized Zwitterionic Highly Branched Poly(β-amino ester)s for Cytoplasmic Protein Delivery

Proteins have tremendous potential for vaccine development and disease treatment, but multiple extracellular and intracellular biological barriers must be overcome before they can exert specific biological functions in the target tissue. The use of polymers as carriers would greatly improve their bioavailability and therapeutic efficiency. Nevertheless, effective protein packaging and cell membrane penetration without causing cytotoxicity is particularly challenging, due largely to the simultaneous distribution of positive and negative charges on protein surface. Here, phosphocholine-functionalized zwitterionic poly(β-amino ester)s, HPAE-D-(±), are developed for cytoplasmic protein delivery. The zwitterionic phosphocholine is capable of binding to both proteins and the cell membrane to facilitate protein packaging and nanoparticle cellular uptake. Compared to amine-functionalized HPAE-E-(+) and carboxylic acid-functionalized HPAE-C-(−), HPAE-D-(±) exhibits much higher cytoplasmic protein delivery efficiency and lower cytotoxicity. In addition, HPAE-D-(±) are readily degraded in aqueous solution.