Rational Design of Morphology Transformable Oligopeptide Self-Assembly for Specifically Inducing Lysosomal Membrane Permeabilization of Tumor Cell

Engineering the functional peptide self-assembly has been proven effective for drug delivery, creating three-dimensional cell culture media and developing new strategies for disease therapy. However, there are few reports on using peptide assemblies as nanotechnological tools to explore the processes and mechanisms of biology. In this work, to investigate tumor lysosomal membrane permeabilization (LMP)-induced effect, which is considered as a promising but not well-defined strategy for treatment of cancers, we established a tumor-specific LMP model by rational construction of a pH-responsive morphology transformable self-assembly of amphiphilic oligopeptide (AOP), containing -[Arg-Gly-Asp]- (RGD) sequence. In brief, the selected AOP, Benz-(Ala) 6 -Arg-Gly-Asp-NH 2 (Benz-A 6 -RGD), could self-assemble to liposome-like nanostructures (peptosomes) at neutral pH (7.4), and the RGD motifs on the surface of peptosomes could recognize integrins on tumor cells and enhance the following endocytosis; then the lysosomal pH (4.0–5.0) protonized RGD motifs and induced the peptosomes to transform to nanofibers. This transformation produced mechanical forces to directly disturb the membrane of lysosomes so as to initiate LMP. To further enhance the antitumor effect, the LMP-induced cell death was combined with the inhibition of the hot shock protein70 (Hsp70)-mediated self-repair mechanism of tumor cells. A significant synergetic antitumor effect was observed for this combination strategy. In summary, the current study introduces a specific model of tumor cell LMP, which can be used for evaluating the LMP-induced effects on tumor cells, and proves the potential of functional peptide self-assembly for exploring biological processes.