Protein‐Gold Nanoclusters Loaded with Ferrous Ions for Inducing Ferroptosis of Hepatoma Cells

Abstract Ferroptosis driven by the iron‐dependent accumulation of lipid peroxides and subsequent oxidative damage of biological membranes has shown great potential in the treatment of various diseases, especially cancer. However, suffering from the lack of safe and efficient delivery strategies for the unstable ferrous ions (Fe²⁺), the therapeutic efficacy induced by ferroptosis is always unsatisfactory. Herein, a protein‐based nanocomposite (Protein‐Gold Hybrid Materials‐Red, PGHM‐R) is designed as both an Fe²⁺ stabilizer and a carrier for the safe and efficient delivery of Fe²⁺ to hepatoma cells. The conspicuous feature of ferroptosis, such as downregulation of GPX4 and FTH1, upregulation of ASCL4 and NOX1, as well as mitochondrial deformation, is observed in PGHM‐R‐Fe‐treated hepatoma cells, which demonstrate that PGHM‐R‐Fe can effectively trigger ferroptosis of hepatoma cells. More importantly, systematic in vivo therapeutic outcomes demonstrate the low side effects and the high tumor‐inhibiting ratio of 58% of PGHM‐R‐Fe in the tumor model of hepatocellular carcinoma‐bearing mice. This novel strategy for inducing the ferroptosis of cancer cells based on utilizing protein to deliver Fe²⁺ holds great potential in the clinical applications of ferroptosis‐based therapy.