Self‐Assembled Fe‐Phenolic Acid Network Synergizes with Ferroptosis to Enhance Tumor Nanotherapy

Abstract Natural polyphenolic compound rosmarinic acid (RA) has good antitumor activity. However, the distinctive tumor microenvironment, characterized by low pH and elevated levels of glutathione (GSH), enhances the tolerance of tumors to the singular anti‐tumor treatment mode using RA, resulting in unsatisfactory therapeutic efficacy. Targeting nonapoptotic programmed cell death processes may provide another impetus to inhibit tumor growth. RA possesses the capability to coordinate with metal elements. To solve the effect restriction of the above single treatment mode, it is proposed to construct a self‐assembled nanocomposite, Fe‐RA. Under tumor microenvironment, Fe‐RA nanocomposite exerts the characteristics of POD‐like enzyme activity and depletion of GSH, producing a large amount of hydroxyl radical (·OH) while disrupting the antioxidant defense system of tumor cells. Moreover, due to the enhanced permeability and retention effect (EPR), Fe‐RA can transport Fe 2+ to a greater extent to tumor cells and increase intracellular iron content. Causing an imbalance in iron metabolism in tumor cells and promoting cell ferroptosis. The results of the synchrotron X‐ray absorption spectroscopy (XAS) and high‐resolution mass spectrometry (HRMS) prove the successful complexation of Fe‐RA nanocomposite. Density functional theory (DFT) explains the efficient catalytic mechanism of its peroxide‐like enzyme activity and the reaction principle with GSH.