Self-Assembled Peptide Nanostructures for ECM Biomimicry

Abstract

Proteins are functional building blocks of living organisms that exert a wide variety of functions, but their synthesis and industrial production can be cumbersome and expensive. By contrast, short peptides are very convenient to prepare at a low cost on a large scale, and their self-assembly into nanostructures and gels is a popular avenue for protein biomimicry. In this Review, we will analyze the last 5-year progress on the incorporation of bioactive motifs into self-assembling peptides to mimic functional proteins of the extracellular matrix (ECM) and guide cell fate inside hydrogel scaffolds.

Keywords: ECM; RGD; biomaterials; biomimicry; collagen; hydrogels; nanofibrils; peptides; proteins; self-assembly.

Figure 1

Heterochiral peptide self-assembly. l-Phe-d-Leu-l-Phe forms stacks held together by H-bonding between amides (a), and space-fill representations (b,c) show the amphipathic character of the stacks, which display a hydrophobic face with the peptide sidechains (b) and a hydrophilic face with amide bonds (c). Carbon atoms are shown in green, hydrogen in white, nitrogen in blue, and oxygen in red. Reproduced from [45].

Figure 2

(a,b) Molecular structures and self-assembling properties of peptide gelator (Nap-FFRGD) and silk fibroin (SF) for the formation of nanofiber and nanofibril bundle structures individually; (c) illustration of the preparation process for SF-RGD gel from Nap-FFRGD and SF, and its biological functions to enhance osteogenesis of encapsulated mBMSCs for bone regeneration in calvarial defect areas of mice. Reprinted with permission from [67], © 2022 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany.

Figure 3

(a) Chemical structures of two self-assembling short peptides with structural (1) and bioactive (2) roles for the co-assembly into bioadhesive hydrogels (b). (c) AFM image of the co-assembled gel. (d) live-dead cell-microscopy images of the control (1) and the bioadhesive (1 + 2) hydrogels with fibroblasts. (e) Quantification of cell spreading. (f) Adherent cells’ count in the presence of Mn⁺⁺ and a β₁ integrin-blocking antibody (Ab) demonstrates integrin engagement for cell adhesion on the biomaterial and successful ECM mimicry. Adapted from [75].

Figure 4

(a) Scheme of self-assembly of hMSC-encapsulated KLD-Cad/KLD-Scr hydrogels. (b) Photograph of KLD-Cad self-assembled hydrogel (d = 5 mm, h = 2.2 mm) (c) SEM images of KLD (left) and KLD-Cad (right) hydrogels after critical point drying show that the average diameter of self-assembled fiber in the KLD and KLD-Cad hydrogels are approximately 17.6 nm and 20.4 nm, respectively. Reprinted from [91], copyright © 2022, with permission from Elsevier.

Figure 5

Life-like systems are out-of-equilibrium and present several useful features to mimic living tissues. Reproduced from [131], copyright © 2022, with permission from Elsevier.