A pH-Responsive Phase-Transition Polymer with High Serum Stability in Cytosolic Protein Delivery

Polymer-mediated intracellular protein delivery systems are important for the development of protein-based biotechnologies and therapeutics. However, intracellular delivery of cargo proteins in the presence of serum remains challenging due to competitive binding of serum proteins with the polymers. Here, we reported a dendrimer engineered with a high density of 4-diethylaminophenyl groups on the surface to address this issue. The dendrimer showed a pH-responsive phase-transition behavior and could assemble with cargo proteins into stable nanoparticles in serum solutions. It efficiently delivered cargo proteins into living cells, and exhibited a pH-responsive disassembly behavior after cell internalization. As a result, various cargo proteins were delivered into the cytosol of living cells with maintained bioactivity. This study provided a convenient and efficient strategy to design polymers with high serum-tolerance in cytosolic protein delivery.