Golgi apparatus is a major subcellular organelle responsible for drug resistance. Golgi apparatus-targeted nanomechanical disruption provides an attractive approach for killing cancer cells by multimodal mechanism and avoiding drug resistance. Inspired by the poisonous twisted fibrils in Alzheimer's brain tissue and enhanced rigidity of helical structure in nature, we designed transformable peptide C6RVRRF4KY that can self-assemble into nontoxic nanoparticles in aqueous medium but transformed into left-handed helical fibrils (L-HFs) after targeting and furin cleavage in the Golgi apparatus of cancer cells. The L-HFs can mechanically disrupt the Golgi apparatus membrane, resulting in inhibition of cytokine secretion, collapse of the cellular structure, and eventually death of cancer cells. Repeated stimulation of the cancers by the precursors causes no acquired drug resistance, showing that mechanical disruption of subcellular organelle is an excellent strategy for cancer therapy without drug resistance. This nanomechanical disruption concept should also be applicable to multidrug-resistant bacteria and viruses.
Keywords: Golgi apparatus; cancer; helical fibrils; mechanical disruption; peptide self-assembly.