Zwitterionic polymers with high serum tolerance for intracellular protein delivery

Cationic polymers have been widely developed as carriers for intracellular protein delivery, but face tough challenges such as poor serum tolerance and inevitable material toxicity. Here, we present a type of phase-separating polymer with an anionic surface to address the above issues. A cationic dendrimer is first modified with a hydrophobic moiety to obtain a pH-responsive amphiphilic polymer, which is further conjugated with anionic benzenesulphonate at different grafting degrees. The benzenesulphonate modification facilely changes the hydrophobicity of the polymer and reduces the material cytotoxicity. Interestingly, the polymer can co-assemble with cargo proteins to form nanovesicles for intracellular protein delivery. The benzenesulphonate on the polymer surface bolsters the resistance of polymers to serum proteins, allowing the materials to maintain high delivery efficacy in culture media containing abundant serum proteins. This study provides a facile strategy to design materials with high serum tolerance for intracellular protein delivery.