Spatiotemporal Self-Assembly of Peptide Amphiphiles by Carbonic Anhydrase IX-Targeting Induces Cancer-Lysosomal Membrane Disruption

Abstract

To achieve spatiotemporal control, an enzyme-instructed self-assembly system is widely used, but this approach typically has a small effect on cellular fate. In this study, we show that the intralysosomal assembly by a carbonic anhydrase IX (CAIX)-targeting peptide amphiphile (Pep-AT) can control cellular fate with a low therapeutic dose by tuning the surface charge based on pH change. Pep-AT self-assembles into a fibrous aggregate with a negative surface charge in an extracellular environment near CAIX. During endocytosis, it changes into a nanofiber with a positive surface charge at the lysosome. Then, it can disrupt the lysosomal membrane and induce cellular apoptosis. This study demonstrates that a spatiotemporal assembly induced by a cancer enzyme and specific organelle can control the cellular fate of cancer.