Introduction: Due to the concerns raised by the extensive application of PEGylation, polypeptides have stood out as excellent candidates with adequate biocompatibility and biodegradability with tunable hydrophilicity.
Areas covered: In this review, polypeptides with the potential to replace PEGylation have been summarized and their application has been reviewed, including XTEN, PASylation, polysarcosine, zwitterion polypeptides, ELPylation, etc. Besides their strengths, the remaining challenges have also been discussed and the future perspectives have been provided.
Expert opinion: Polypeptides have been applied in the designing of peptide/protein drugs as well as nanomedicines, and some of the pharmaceutics have made it into the clinical trials and got approved. These polypeptides showed similar hydrophilic properties to PEGylation, which increased the hydrodynamic volumes of protein drugs, reduced kidney elimination, decreased protein-polymer interaction and potentially improved the drug delivery efficiency due to the extended circulation time in the system. Moreover, they demonstrated superior biodegradability and biocompatibility, compensating for the deficiencies for polymers such as PEG.
Keywords: Polypeptides; drug delivery; hydrophilic polymers; long circulating; nanomedicine; protein/peptide drugs.