Biomaterials based on the assembly of peptides and proteins are currently being developed for a wide range of biomedical applications, from cell encapsulation and 3D culture to vaccines and other immunotherapies. Each of these biological contexts is highly complex and multi-factorial, where specific phenotypes arise from a diversity of biomaterial-related inputs.<br/><br/>To interface this complexity, and to elicit highly specific phenotypes from biology, we have been developing modular materials based on the assembly of peptides and proteins, where specific factors can be mixed together with high degrees of control and delivered to biological systems. Here we will describe recently designed protein and peptide hybrid materials where combinations of expressed proteins or peptide epitopes can be induced to assemble into nanofibers and hydrogels with exact stoichiometries of the polypeptides. New applications of these materials will be described, towards 3D cell culture, vaccines, and immunomodulatory therapies for chronic inflammation.<br/><br/>Towards defined matrices for 3D cell culture, fibronectin domains were expressed in E. coli in tandem with the recently reported “β-tail” tag, which allows insertion of whole folded proteins into β-sheet peptide nanofibers. Using Western blotting and pulldown assays, co-assembly of specific amounts of fibronectin domains into peptide nanofibers was observed, and self-assembled fibrils incorporating the proteins facilitated the culture of LNCaP cells, a prostate cancer cell line that is challenging to grow in more traditional matrices such as Matrigel. Towards immunomodulating materials, we expressed the cytokine interferon-g (IFN-γ) in tandem with the β-tail tag. Using pull-down and macrophage stimulation assays, we found that active IFN-γ could be inserted into the nanofibers at titratable doses, enabling subsequent use in polarizing immune responses against the materials. In a third example, adjusting the phenotype of vaccine responses, we found that self-assembling peptide nanofibers allowed the precise adjustment of T cell epitopes and B cell epitopes in the materials, and that systematic variation of the epitope content could be used to optimize antibody responses in a vaccine against methicillin-resistant S. aureus (MRSA). Collectively, these 3 examples demonstrate the breadth of biomedical applications that can be served using supramolecular materials able to integrate precise combinations of different biological cues.

Fibrillar protein and peptide co-assemblies: Design and applications in medicine

249th National Meeting (2015)

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