Synthetic polypeptides from the ring-opening polymerization of N-carboxyanhydrides (NCAs) are one of the most important biomaterials. The unique features of these synthetic polypeptides, including their chemical diversity of side chains and their ability to form secondary structures, enable their broad applications in the field of gene delivery, drug delivery, bio-imaging, tissue engineering, and antimicrobials. In this review article, we summarize the recent advances in the design of polypeptide-based supramolecular structures, including complexes with nucleic acids, micelles, vesicles, hybrid nanoparticles, and hydrogels. We also highlight the progress in the chemical design of functional polypeptides, which plays a crucial role to manipulate their assembly behaviours and optimize their biomedical performances. Finally, we conclude the review by discussing the future opportunities in this field, including further studies on the secondary structures and cost-effective synthesis of polypeptide materials.

Synthetic polypeptides derived from the ring-opening polymerization of N-carboxyanhydrides can spontaneously fold into stable secondary structures under specific environmental conditions. These secondary structures and their dynamic transitions play an important role in regulating the properties of polypeptides in self-assembly, catalysis, polymerization, and biomedical applications. Here, we review the current strategies to modulate the secondary structures, and highlight the conformation-specific dynamic properties of synthetic polypeptides and the corresponding materials. A number of mechanistic studies elucidating the role of secondary structures are discussed, aiming to provide insights into the new designs and applications of synthetic polypeptides. We aim for this article to bring to people's attention synthetic polymers with ordered conformations, which may exhibit association behaviors and material properties that are otherwise not found in polymers without stable secondary structures.

Significance: Biomacromolecules are synthesized in cells with high precision, although the cellular environment contains numerous molecules and species other than the building blocks. In contrast, even the state-of-the-art chemical synthesis of macromolecules is exclusively carried out under a specific condition containing only clean, essential starting materials to minimize side reactions. Inspired by ribozyme-catalyzed protein synthesis, we report here controlled polypeptide synthesis by nonpurified N -carboxyanhydride monomers in an oil/water biphasic system that mediates impurity segregation and enables very fast polymerization that outpaces competing side reactions.

The recent advances in accelerated polymerization of N-carboxyanhydrides (NCAs) enriched the toolbox to prepare well-defined polypeptide materials. Herein we report the use of crown ether (CE) to catalyze the polymerization of NCA initiated by conventional primary amine initiators in solvents with low polarity and low hydrogen-bonding ability. The cyclic structure of the CE played a crucial role in the catalysis, with 18-crown-6 enabling the fastest polymerization kinetics. The fast polymerization kinetics outpaced common side reactions, enabling the preparation of well-defined polypeptides using an α-helical macroinitiator. Experimental results as well as the simulation methods suggested that CE changed the binding geometry between NCA and propagating amino chain-end, which promoted the molecular interactions and lowered the activation energy for ring-opening reactions of NCAs. This work not only provides an efficient strategy to prepare well-defined polypeptides with functionalized C-termini, but also guides the design of catalysts for NCA polymerization.