Enzyme-Instructed Peptide Assemblies Selectively Inhibit Bone Tumors

Summary Alkaline phosphatase (ALP) contribute to immunosuppression in solid tumors, but they, unfortunately, are "undruggable." Here, we report enzyme-instructed assembly of peptides for selectively inhibiting the tumors that overexpress ALP. We developed a precursor with two parts: amphiphilic, self-assembling peptides joined to a hydrophilic block (i.e., tyrosine phosphate). ALP, overexpressed on and in osteosarcoma cancer cells (e.g., Saos-2), cleaves the phosphates from the tyrosine residue of the precursor and triggers the self-assembly of the resulting peptides. Being selectively formed on and inside the cancer cells, the peptide assemblies induce the cancer cell death and efficiently inhibit the tumor growth in an orthotopic osteosarcoma mouse model without harming normal organs. Accordingly, the peptide assemblies significantly improve the survival ratio of metastatic-tumor-bearing mice. Without relying on inhibiting ALP, this approach integrates enzyme reaction and molecular self-assembly for generating peptide fibrils as potential anticancer therapeutics.