Unstructured polypeptides as a versatile drug delivery technology

Although polyethylene glycol (PEG), or "PEGylation" has become a widely applied approach for improving the efficiency of drug delivery, the immunogenicity and non-biodegradability of this synthetic polymer have prompted an evident need for alternatives. To overcome these caveats and to mimic PEG-or other natural or synthetic polymers-for the purpose of drug half-life extension, unstructured polypeptides are designed. Due to their tunable length, biodegradability, low immunogenicity and easy production, un-structured polypeptides have the potential to replace PEG as the preferred technology for therapeutic protein/peptide delivery. This review provides an overview of the evolution of unstructured polypeptides, starting from natural polypeptides to engineered polypeptides and discusses their characteristics. Then, it is described that unstructured polypeptides have been successfully applied to numerous drugs, including peptides, proteins, antibody fragments, and nanocarriers, for half-life extension. Innovative applications of unstructured peptides as releasable masks, multimolecular adaptors and intracellular delivery carriers are also discussed. Finally, challenges and future perspectives of this promising field are briefly presented.Statement of significance Polypeptide fusion technology simulating PEGylation has become an important topic for the development of long-circulating peptide or protein drugs without reduced activity, complex processes, and kidney in-jury caused by PEG modification. Here we provide a detailed and in-depth review of the recent advances in unstructured polypeptides. In addition to the application of enhanced pharmacokinetic performance, emphasis is placed on polypeptides as scaffolders for the delivery of multiple drugs, and on the prepa-ration of reasonably designed polypeptides to manipulate the performance of proteins and peptides. This review will provide insight into future application of polypeptides in peptide or protein drug develop-ment and the design of novel functional polypeptides.(c) 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.