Impact of Amphiphilic Balance on Nano-Bio Interactions of Peptide Amphiphile Nanostructures

Self-assembled peptide amphiphile (PA)-based nanostructures are promising biomaterials with their biocompatibility and highly tunable physical and chemical properties. Despite this promise, the interactions of PA nanostructures with biological systems have remained largely unexplored. Here, we investigate nano-bio interactions of self-assembled PA nanostructures using a series of PAs with varying amphiphilicities, achieved by tuning the hydrophilicity of the peptide backbone and payloads attached to them. We show that, while PAs with hydrophilic peptide backbones and payloads mostly disassembled in blood plasma, increasing overall hydrophobicity improved their stability. We also report that disassembled PAs can bind to blood biomolecules and binding shifted from albumin to lipoproteins with increasing hydrophobicity. In addition, we show that the membrane-binding affinity of PAs increases with increasing PA hydrophobicity, which also induces membrane disruption and cytotoxicity. The results of this study highlight the critical role of the overall amphiphilic balance of PAs on their interactions with biological molecules and cell membranes.