A pH/STEAP Cascade‐Responsive Nanomedicine with Self‐Supplied Peroxide for Precise Chemodynamic Therapy

Abstract Self‐supply of peroxo compounds has been regarded as a promising strategy to enhance Fenton chemistry‐based chemodynamic therapy (CDT). However, the inherent selectivity of CDT will be affected after introducing peroxide‐supplementing functionality into chemodynamic agents due to the lack of ability to distinguish cancer cells from normal cells. Here, an intelligent CDT nanomedicine is reported with both cascade‐responsive and peroxide self‐supplying performances for specific and efficient cancer treatment. Upon endocytosis into acidic endo/lysosomes, the CDT nanomedicine comprising methyl linoleate hydroperoxide (MLH)‐loaded amorphous iron oxide nanoparticles (AIO@MLH NPs) can be decomposed to release MLH and Fe 3+ that is further reduced into Fe 2+ by endo/lysosomal six‐transmembrane epithelial antigen of the prostate (STEAP) with metalloreductase activity, enabling the occurrence of Fenton‐type reaction between high‐active Fe 2+ and MLH for free radical generation, which causes endo/lysosomal damage and cancer cell apoptosis. Noteworthily, AIO@MLH NPs exhibit potent chemodynamic cytotoxicity to cancerous cells rather than non‐cancerous cells benefiting from the overexpressed STEAP in multiple cancers, thereby leading to precise tumor CDT. This work highlights the use of endogenous STEAP to improve the selectivity of peroxide self‐supplying chemodynamic agents and paves the way for the development of precision medicine.