Protein-, (Poly)peptide-, and Amino Acid-Based Nanostructures Prepared via Polymerization-Induced Self-Assembly

Abstract

Proteins and peptides, built from precisely defined amino acid sequences, are an important class of biomolecules that play a vital role in most biological functions. Preparation of nanostructures through functionalization of natural, hydrophilic proteins/peptides with synthetic polymers or upon self-assembly of all-synthetic amphiphilic copolypept(o)ides and amino acid-containing polymers enables access to novel protein-mimicking biomaterials with superior physicochemical properties and immense biorelevant scope. In recent years, polymerization-induced self-assembly (PISA) has been established as an efficient and versatile alternative method to existing self-assembly procedures for the reproducible development of block copolymer nano-objects in situ at high concentrations and, thus, provides an ideal platform for engineering protein-inspired nanomaterials. In this review article, the different strategies employed for direct construction of protein-, (poly)peptide-, and amino acid-based nanostructures via PISA are described with particular focus on the characteristics of the developed block copolymer assemblies, as well as their utilization in various pharmaceutical and biomedical applications.

Keywords: biomaterials; block copolymers; nanostructures; polymerization-induced self-assembly; polypeptides; proteins; protein–polymer conjugates; α-amino acids.

Figure 1

(A) Synthesis of BSA-g-PHPMA hybrid nano-objects via aqueous RAFT-mediated photo-PISA and subsequent in situ encapsulation of DOX and DNA. Adapted with permission from reference [57]. Copyright 2017 American Chemical Society. (B) Synthesis of HSA-g-PHPMA hybrid nano-objects via aqueous ATRP-mediated PISA and subsequent in situ encapsulation of green fluorescence protein (GFP) to form GFP-loaded vesicles. Reproduced with permission from reference [58]. Copyright 2017 American Chemical Society.

Figure 2

Synthesis of GOx/HRP-g-PHPMA hybrid co-micelles via aqueous ATRP-mediated PICA (top), and representative TEM images of developed GOx-, HRP-, and GOx/HRP-based spherical nanoparticles (bottom). Adapted with permission from reference [60]. Copyright 2019 American Chemical Society.

Figure 3

Schematic diagram of ROMPISA conducted using an oligo(ethylene glycol)-based PNB stabilizer block (PNB-OEG, blue) and a peptide-based core-forming norbornene macromonomer (NB-GPLGLAGGERDG, red). Reproduced with permission from reference [72]. Copyright 2017 American Chemical Society.

Figure 4

(A) Synthesis of P(GMA-stat-(MAm-GFF))-b-PHPMA block copolymer nanostructures via aqueous RAFT-mediated PISA (top), and representative TEM images of developed dendritic fibers (bottom). Adapted with permission from reference [77]. Copyright 2020 American Chemical Society. (B) Synthesis of PGMA-b-P(MAm-FGD) block copolymer nanostructures via aqueous RAFT-mediated PISA (top), and representative TEM images of prepared dendritic fibers (bottom). Adapted with permission from reference [80]. Copyright 2021 Royal Society of Chemistry.

Figure 5

(A) Synthesis of PSar-b-PHPMA diblock copolymer nano-objects via aqueous RAFT-mediated photo-PISA. (B) Phase diagram and representative TEM images for PSar-b-PHPMA diblock copolymer nano-objects as a function of total solids concentration and core-block DP. Reproduced with permission from reference [89]. Copyright 2018 American Chemical Society.

Figure 6

(A) Synthesis of PBLAEMA-b-PBzMA diblock copolymer nano-objects via alcoholic RAFT-mediated PISA and subsequent Boc-group cleavage for the preparation of respective PLAEMA-b-PBzMA nanostructures. (B) Representative SEM images of PBLAEMA-b-PBzMA vesicles and their corresponding lower-order nano-object morphologies in methanol and water, following in situ Boc-group deprotection of PBLAEMA, along with a schematic illustration of the process. Reproduced with permission from reference [102]. Copyright 2015 Royal Society of Chemistry.