Polyresorcinols for intracellular protein delivery

Developing protein delivery systems holds tremendous promise for the next-generation of protein-related biotechniques and biotherapeutics. Polycatechols inspired from nature polyphenols such as epigallocatechin gallate represent a class of polymers with highly efficacy in cytosolic protein delivery. Besides catechol, there are other benzenediol structures with two hydroxyls on an aromatic ring such as resorcinol and hydroquinone, and their behaviors in protein binding and intracellular delivery are yet unknown. Here, we firstly reported a type of polyresorcinols by grafting resorcinol moieties on cationic dendrimers for efficient cytosolic protein delivery. The materials exhibited comparable protein delivery efficacy with polycatechols but much higher stability towards oxidation in air. The resorcinol modification greatly improved the protein binding, cellular internalization, and endosomal disruption of the cationic polymer and reduced its cytotoxicity as well. The obtained polyresorcinols delivered various native proteins into the cytoplasm with maintained protein bioactivities, and successfully delivered a model antigen ovalbumin into dendritic cells to induce antigen cross-presentation for the treatment of B16-OVA melanoma in vivo. This study gives new insights into the physicochemical behaviors of phenolic polymers and developed a class of polyresorcinols for efficient cytosolic protein delivery.