Functionalization of polymers for intracellular protein delivery

With the growing demand for clinically reliable therapeutics, traditional small molecule drugs are increasingly limited by their short circulation duration, low bioavailability, and poor targeting. Protein drugs, on the other hand, have gained popularity due to their high activity, high specificity, low cytotoxicity, and distinct biological function. Especially, monoclonal antibodies are among the top 10 drugs in global sales. However, protein drugs have limitations such as complex and unstable structure, immune clearance caused by antigen fragments on the surface, and inability to penetrate cell membranes, which severely restrict intracellular delivery. Using carriers can greatly enhance the stability of protein drugs, prevent immune clearance, and facilitate their cellular uptake and cytosolic release. Polymers are commonly used for delivering small molecules, DNA, and RNA. However, developing polymers for protein delivery with high efficiency and low cytotoxicity still faces several challenges, including poor protein binding ability, membrane impermeability, and low endo/lysosomal escape efficiency. Functionalizing polymers with specific components such as fluorine, boron, guanidine, heterocycles, and multicomponents can improve polymer-protein interaction, cell membrane penetration, endo/lysosomal escape, and biocompatibility. This review provides an overview of strategies for polymer functionalization and their effects on protein delivery. It also discusses trends and challenges in developing polymer carriers for protein delivery.