Cell-Penetrating Cross-β Peptide Assemblies with Controlled Biodegradable Properties

Although self-assembled peptide nanostructures (SPNs) have shown potential as promising biomaterials, there is a potential problem associated with the extremely slow hydrolysis rate of amide bonds. Here, we report the development of cell-penetrating cross-β SPNs with a controllable biodegradation rate. The designed self-assembling β-sheet peptide incorporating a hydrolyzable ester bond (self-assembling depsipeptide; SADP) can be assembled into bilayer β-sandwich one-dimensional (1D) fibers similarly to conventional β-sheet peptides. The rate of hydrolysis can be controlled by the pH, temperature, and structural characteristics of the ester unit. The 1D fiber of the SADP transforms into vesicle-like 3D structures when the hydrophilic cell-penetrating peptide segment is attached to the SADP segment. Efficient cell internalization of the 3D nanostructures was observed, and we verified the intracellular degradation and disassembly of the biodegradable nanostructures. This study illustrates the potential of biodegradable cross-β SPNs and provides a valuable toolkit that can be used with self-assembling peptides.