Title: Metal–Phenolic Network-Based Nanocomplexes that Evoke Ferroptosis by Apoptosis: Promoted Nuclear Drug Influx and Reversed Drug Resistance of Cancer

Abstract: Discovering new pathways for overcoming multidrug resistance (MDR) of cancer is important to the development of chemotherapy. Herein, by mixing the metal–phenolic network formed by tannic acid and Fe³⁺ with the doxorubicin (DOX)-loaded dendrimer (Den), we prepare the Den–DOX–tannic acid–Fe³⁺ (DDTF) nanocomplex which can combat MDR of cancer cells via an apoptosis/ferroptosis hybrid pathway. The elevated reactive oxygen species (ROS) level caused by DOX-induced apoptosis sensitizes cancer cells to the Fenton reaction-induced ferroptosis and improves the efficiency of chemodynamic therapy (CDT). More interestingly, DDTF can preferably kill the cancer cells over the normal ones, possibly due to the higher hydrogen peroxide content in cancer cells. Besides, DDTF can efficiently transport DOX to the cytosol by evading the drug efflux transporters that are located on the plasma membranes of drug-resistant cancer cells and deliver DOX to the nuclei with the help of Fenton reaction-induced ferroptosis. Afterward, the Fenton reaction- and DOX-induced excessive ROS ultimately kill the drug-resistant cancer cells. In vivo experiments demonstrate that DDTF efficiently targets the tumor after intravenous injection and almost completely eliminates the tumor tissue. This work may foster the development of novel strategies for realizing cancer CDT and overcoming cancer MDR.