Vitamin B2‐Based Ferroptosis Promoter for Sono‐Enhanced Nanocatalytic Therapy of Triple‐Negative Breast Cancer

Abstract Ferroptosis featured by iron‐dependent lipid peroxidation plays a critical role in tumor regression, offering an alternative therapeutic target for the treatment of aggressive triple‐negative breast cancer. However, the traditional delivery strategy to enrich iron deposition is limited in producing a surplus of lipid oxidation because of the aggressive antioxidant response established in solid tumors. Here, vitamin B 2 ‐ferric chloride nanocomplex self‐assembled through the coordination of ferric iron and hydroxy groups to simultaneously promote iron accumulation and oxidative stress is employed. It is observed that the self‐assembly nanostructures with appropriate size enable effective delivery of the therapeutic agents to the tumor site and cancer cells. More importantly, sonosensitizer vitamin B2 and ferric chloride cooperatively facilitate the production of reactive oxygen species and amplify nanocatalytic therapy. To further disrupt the antioxidant system, metformin with solute carrier family 7 member 11 inhibitory activity is used to synergistically boost ferroptosis of tumor cells. The combinational ferroptosis promoter exhibits augmented nanocatalytic antitumor efficacy in 4T1 tumor‐bearing mice with negligible adverse effects. Taken together, this study may provide a novel paradigm of self‐assembled vitamin B2‐ferric nanocomplex for ferroptosis regulation.