Polymers for cytosolic protein delivery

Cytosolic protein delivery offers opportunities to develop protein-based therapeutics specifically modulate intracellular processes, especially those linked to `undruggable' targets. Since protein molecules are generally membrane-impermeable due to their macromolecular nature and hydrophilic property, carriers are needed to facilitate protein transport through cell membranes. Current delivery techniques usually require chemical modification or genetically engineering on cargo proteins to strengthen the binding affinity between proteins and the carriers. However, these approaches are usually accompanied with complicated syntheses, and the bioactivity of proteins might be irreversibly changed after modification. In this review, we discussed recent advances in the rational design of polymers for cytosolic delivery of native proteins with distinct isoelectric points and sizes. Functional ligands were grafted onto cationic polymers to strengthen the binding affinity between polymers and proteins, and/or to reduce the charge repulsion between cationic polymers during the formation of polymer/protein complexes. The principles of developed polymers in cytosolic protein delivery were intensively discussed. Furthermore, the possibility of developed polymers in the delivery of therapeutic proteins to treat diseases in vivo was evaluated. We hope to provide theoretical and technical supports to the development of polymers for cytosolic protein delivery.