Soluble Assemblies in the Fibrillation Pathway of Prion-Inspired Artificial Functional Amyloids are Highly Cytotoxic.

Amyloids are associated with human disease. However, they are also exploited by nature for functional purposes. Functional amyloids have inspired amyloid-based biomaterials for different nanotechnologies. Early soluble species in the fibrillation pathway seem to be the primary elicitors of cytotoxicity, instead of fibrils. Organisms have evolved dedicated mechanisms to avoid toxicity during the assembly of functional amyloids. In their absence, artificial amyloid-based nanomaterials might also produce toxic intermediates. We show here that even when the building blocks of artificial amyloids are small, polar, and compositionally simple, their early soluble assemblies are extremely cytotoxic, causing cell death through mechanisms identical to those of disease-associated proteins. Our results raise safety concerns about the use of non-natural amyloid-based materials without a rigorous characterization of their fibrillation pathway. Besides, the simple, cheap, and easy to synthesize peptides we use here might turn very useful to understand the molecular determinants behind amyloid cytotoxicity.