Amphiphilic Peptide Nanorods Based on Oligo-Phenylalanine as a Biocompatible Drug Carrier

Peptide nanostructure has been widely explored for drug-delivery systems in recent studies. Peptides possess comparatively lower cytotoxicity and are more efficient than polymeric carriers. Here, we propose a peptide nanorod system, composed of an amphiphilic oligo-peptide RH₃F₈ (Arg-His₃-Phe₈), as a drug-delivery carrier. Arginine is an essential amino acid in typical cell-penetration peptides, and histidine induces endo- and lysosomal escape because of its proton sponge effect. Phenylalanine is introduced to provide rich hydrophobicity for stable self-assembly and drug encapsulation. The self-assembled structure of RH₃F₈ showed nanorod-shaped morphology, positive surface charge, and retained formation in water for 35 days. RH₃F₈, labeled with Nile Red, showed high cellar uptake and accumulation in both cytoplasm and nucleus. The RH₃F₈ nanorods demonstrated negligible cytotoxicity, as shown by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), and hemolysis assays. To confirm the efficiency of drug delivery, curcumin was encapsulated in the RH₃F₈ nanorod system (RH₃F₈-Cur). RH₃F₈-Cur showed high encapsulation efficiency (24.63%) under the conditions of 200 μM curcumin. The RH₃F₈-Cur retained nanoscale size and positive surface charge, similar to those of the empty RH₃F₈ nanorods. RH₃F₈-Cur displayed a robust anticancer effect in HeLa and A549 cells, and inhibited the proliferation of cancer cells in a zebrafish model. These results indicate that the RH₃F₈ nanorods may be a promising candidate for a safe and effective drug-delivery system.