A Biomimetic Manganese Complex Synergistically Disables Antioxidant Defenses and Amplifies Oxidative Stress to Potentiate Ferroptosis in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains a lethal malignancy with limited therapeutic options in advanced stages. Here, we report a biomimetic manganese-based complex (MSM) engineered to selectively target HCC cells and potently induce ferroptosis through a dual mechanism: disabling cellular antioxidant defenses and amplifying oxidative stress. The complex undergoes glutathione (GSH)-triggered disassembly within tumor cells, releasing Mn²⁺ ions and sulfasalazine (SAS). Mn²⁺ catalyzes a Fenton-like reaction, generating a burst of reactive oxygen species (ROS), while SAS inhibits the System Xc^-/GSH/GPX4 axis, blocking both de novo GSH synthesis and redox homeostasis. This synergistic action depletes intracellular GSH, promotes lethal lipid peroxidation, and drives robust ferroptosis. Furthermore, the GSH-responsive release of Mn²⁺ enables activatable T₁-weighted magnetic resonance imaging, allowing real-time monitoring of treatment response. Our work presents an integrated theranostic strategy that combines precise ferroptosis induction with non-invasive imaging, offering a promising approach for the management of advanced HCC.