Dual Enzyme-Responsive Zwitterionic Peptide for High Cancer Selectivity via Intralysosomal Self-Assembly

The major challenges in cancer chemotherapy are the severe side effects of the chemotherapeutic drugs due to their off-target toxicity to normal cells. Peptide amphiphiles capable of enzyme-instructed intracellular self-assembly have emerged as biocompatible alternatives, yet achieving high cancer selectivity remains challenging. Herein, we reported a dual enzyme-responsive zwitterionic peptide assembly, which undergoes matrix metalloproteinase induced-disassembly and cathepsin B instructed-assembly to form the fiber in the cancerous lysosome. This sequential enzymatic process induces lysosomal membrane permeabilization and cancer cell death at low micromolar concentrations while remaining inactive in normal cells lacking these enzymes. As a result, very high cancer selectivity (cancer selectivity index of 64.1) is achieved with our designed peptide amphiphiles. The peptide amphiphile also shows significant tumor regression with low doses and no <i>in vivo</i> toxicity tested in the human colorectal adenocarcinoma cell line (HT-29) xenograft tumor model.