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 (Fe 2+ ), 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 Fe 2+ stabilizer and a carrier for the safe and efficient delivery of Fe 2+ 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 Fe 2+ holds great potential in the clinical applications of ferroptosis-based therapy.

Ferroptosis Nanomedicine: Clinical Challenges and Opportunities for Modulating Tumor Metabolic and Immunological Landscape

“…After intravenous injection of PGHM-R-Fe in tumor-bearing mice, the nanocomplex could effectively accumulate in the targeted lesion owing to the enhanced permeability and retention effects and further internalized by cells. 154 Interestingly, PGHM-R-Fe could upregulate NOX1 activity to elevate ROS stress, which would boost the Fe 2+mediated Fenton reaction efficiency to promote the generation of hydroxyl radicals. Meanwhile, the PGHM-R-Fe treatment also substantially upregulated the expression of ACSL4 to enhance the production of ferroptosis-susceptible PUFAs, which further improved the sensitivity of tumor cells to ROS attack for elevated ferroptosis-dependent antitumor efficacy.…”

“…Bovine serum albumin (BSA), gold nanoclusters and amino acids were first reacted to form nanoparticulate substrates, followed by the loading of DOX, pGal-sGFP plasmid vectors and Fe 2+ to form PGHM-R-Fe. After intravenous injection of PGHM-R-Fe in tumor-bearing mice, the nanocomplex could effectively accumulate in the targeted lesion owing to the enhanced permeability and retention effects and further internalized by cells . Interestingly, PGHM-R-Fe could upregulate NOX1 activity to elevate ROS stress, which would boost the Fe 2+ -mediated Fenton reaction efficiency to promote the generation of hydroxyl radicals.…”