Nowadays, how to improve the selectivity of
chemotherapy drugs and reduce their side effects is still a significant challenge for
cancer research. Although
enzyme-instructed self-assembly (EISA) has provided a promising approach for selective
cancer therapy, the application of EISA is still suffering from requiring much higher concentrations for inhibiting
cancer cells. Therefore, new strategies are needed to maximize the anticancer efficacy and preserve the selectivity of EISA. In this study, we rationally designed and synthesised a novel
peptide-based
prodrug molecule, NapGDFDFpYSV, combining EISA with the YSV anticancer
peptide. The activity of the
prodrug molecule was remarkably reduced by masking "Y" with a phosphoryl (-PO3) group and was recovered through dephosphorylation in situ by
alkaline phosphatase (ALP) catalysis. The resulting monomer, NapGDFDFYSV, as a hydrogelator further self-assembled into the nanodrug on the cell surface, resulting in enhanced cellular uptake and selective high cytotoxicity to cells overexpressing ALP via action on
histone deacetylase. Moreover, the required cell inhibition concentration of NapGDFDFpYSV was much lower than its critical
micelle concentration (CMC), exhibiting outstanding advantages compared with separately used EISA without the anticancer
peptide. Our study provides a new strategy to improve the cytotoxicity selectivity and bioactivity of
chemotherapy drugs as well as the anticancer efficiency of EISA.