Expanding the chemical repertoire of protein-based polymers for drug-delivery applications

Expanding the chemical repertoire of natural and artificial protein-based polymers (PBPs) can enable the production of sequence-defined, yet chemically diverse, biopolymers with customized or new properties that cannot be accessed in PBPs composed of only natural amino acids. Various approaches can enable the expansion of the chemical repertoire of PBPs, including chemical and enzymatic treatments or the incorporation of unnatural amino acids. These techniques are employed to install a wide variety of chemical groups—such as bio-orthogonally reactive, cross-linkable, post-translation modifications, and environmentally responsive groups—which, in turn, can facilitate the design of customized PBP-based drug-delivery systems with modified, fine-tuned, or entirely new properties and functions. Here, we detail the existing and emerging technologies for expanding the chemical repertoire of PBPs and review several chemical groups that either demonstrate or are anticipated to show potential in the design of PBP-based drug delivery systems. Finally, we provide our perspective on the remaining challenges and future directions in this field.