In Situ Construction of Ferrocene-Containing Membrane-Bound Nanofibers for the Redox Control of Cancer Cell Death and Cancer Therapy

Precisemanipulation of cancer cell death by harnessingreactiveoxygen species (ROS) is a promising strategy to defeat malignant tumors.However, it is quite difficult to produce active ROS with spatialprecision and regulate their biological outcomes. We succeed here in selectively generating short-lived and lipid-reactive hydroxylradicals ((OH)-O-& BULL;) adjacent to cancer cell membranes,successively eliciting lipid peroxidation and ferroptosis. DiFc-K-pY,a phosphorylated self-assembling precursor that consists of two branchedFc moieties and interacts specifically with epidermal growth factorreceptor, can in situ produce membrane-bound nanofibersand enrich ferrocene moieties on cancer cell membranes in responseto alkaline phosphatase. Within the acidic tumor microenvironment,DiFc-K-pY nanofibers efficiently convert tumoral H2O2 to active (OH)-O-& BULL; around the target cell membranesvia Fenton-like reactions, leading to lipid peroxidation and ferroptosiswith good cellular selectivity. Our strategy successfully preventstumor progression with acceptable biocompatibility through intratumoraladministration.

Automated summary

Manipulating cancer cell death through precise control of reactive oxygen species (ROS) is a promising strategy for treating malignant tumors. However, generating active ROS with spatial precision and regulating their biological outcomes is challenging. In this study, we successfully generated short-lived and lipid-reactive hydroxyl radicals ((OH)-O-·) adjacent to cancer cell membranes, leading to lipid peroxidation and ferroptosis. By using a phosphorylated self-assembling precursor, we selectively produced membrane-bound nanofibers and enriched ferrocene moieties on cancer cell membranes, resulting in the conversion of tumoral H2O2 to active (OH)-O-· through Fenton-like reactions. Our strategy effectively prevented tumor progression with good cellular selectivity and acceptable biocompatibility through intratumoral administration.