Rationally Designed Enzyme-Resistant Peptidic Assemblies for Plasma Membrane Targeting in Cancer Treatment.

Peptides are being increasingly important for subcellular targeted cancer treatment to improve specificity and reverse multidrug resistance. However, there has been yet any report on targeting plasma membrane (PM) through self-assembling peptides. W e have developed a simple synthetic peptidic molecule (tF4). W e revealed that tF4 is carboxyl esterase-resistant and self-assembles into vesical nanostructures. Importantly, tF4 assemblies interacted with PM through orthogonal hydrogen bonding and hydrophobic interaction to regulate cancer cellular functions. Mechanistically, tF4 assemblies induced stress fibre formation, cytoskeleton reconstruction, and death receptor 4/5 (DR4/5) expression in cancer cells. DR4/5 triggered extrinsic caspase-8 signalling cascade, resulting in cell death. O ur results provide a new strategy for developing enzyme-resistant and PM-targeting peptidic molecules against cancer. This article is protected by copyright. All rights reserved.