Enzymatically‐Formed Peptide Assemblies Sequestrate Proteins and Relocate Inhibitors for Selectively Killing Cancer Cells

Here we show that enzymatic reaction generates peptide assemblies to sequestrate proteins for selectively killing cancer cells. A phosphopeptide bearing the antagonistic motif (AVPI) to the inhibitors of apoptotic proteins (IAPs) enters cancer cells and normal cells via caveolin-dependent endocytosis and macropinocytosis, respectively. The AVPI-bearing peptide assemblies in the cytosol sequestrate IAPs and sensitize the cancer cells to bortezomib (BTZ), a proteasome inhibitor, but rescue the normal cells (i.e., HS-5) by trafficking the BTZ into lysosomes. Alkaline phosphatase (ALP) acts as a context-dependent signal for trafficking the peptide/BTZ assemblies and selectively inducing the death of the cancer cells. The assemblies of AVPI exhibit enhanced proteolytic resistance. This work, being the first example of utilizing the endocytic difference of enzymatically formed peptide assemblies for selective killing cancer cells, promises a new way to develop selective cancer therapeutics.