Glutathione depletion under hypoxia via a birnessite-type manganese oxide nanozyme inducing immunogenic ferroptosis for magnetic resonance imaging guided cancer therapy

Glutathione (GSH) depletion can inhibit glutathione peroxidase 4 (GPX4) activity, leading to the accumulation of lipid peroxides and the induction of ferroptosis. However, achieving efficient GSH depletion under the hypoxic conditions typical of tumor microenvironments using non-precious metal-based materials remains a significant challenge for effective cancer therapy. Methods: experiments using 4T1 tumor models were conducted to assess the nanozyme's ability to induce cytotoxicity, corresponding mechanism, and function as a magnetic resonance imaging contrast agent. Results: studies confirmed that CMO induced ferroptosis and immunogenic cell death in 4T1 cells. This process promoted dendritic cell maturation and T-cell infiltration, successfully eliciting a robust systemic antitumor immune response. Furthermore, CMO exhibited significant magnetic resonance imaging capabilities, validating its theranostic potential. Conclusions: The study presents a non-precious metal-based birnessite-type manganese oxide nanozyme capable of ultrafast GSH consumption under hypoxia. This platform effectively activates immunogenic ferroptosis and offers strong potential for magnetic resonance imaging-guided cancer immunotherapy.