Theranostics · 2026
Glutathione depletion under hypoxia via a birnessite-type manganese oxide nanozyme inducing immunogenic ferroptosis for magnetic resonance imaging guided cancer therapy.
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Sun Huilin, Li Bo, Qiu Lin, Zhao Yufeng, Wang Xin, Zhu Chenxian, Zhang Haonan, Wang Xiang, Bai Yang, Wang Jianhao
Аннотация
UNLABELLED: 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: We synthesized a two-dimensional birnessite-type nanosheet-like manganese oxide nanozyme (CMO). The multienzymatic activity and GSH consumption capacity of CMO were evaluated. Density functional theory calculations and material characterizations were utilized to investigate the mechanism of GSH oxidation under varying oxygen levels. In vitro and in vivo 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: CMO demonstrated ultrafast GSH depletion, consuming GSH within 1 minute at a concentration of 20 μg/mL. Importantly, this rapid depletion capacity was not suppressed under hypoxic conditions. Theoretical and experimental analyses revealed that GSH oxidation was driven by the reduction of Mn and the sacrificing of lattice oxygen, which generated oxygen vacancies and a rougher material surface. In vitro and in vivo 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.
METHODS: We synthesized a two-dimensional birnessite-type nanosheet-like manganese oxide nanozyme (CMO). The multienzymatic activity and GSH consumption capacity of CMO were evaluated. Density functional theory calculations and material characterizations were utilized to investigate the mechanism of GSH oxidation under varying oxygen levels. In vitro and in vivo 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: CMO demonstrated ultrafast GSH depletion, consuming GSH within 1 minute at a concentration of 20 μg/mL. Importantly, this rapid depletion capacity was not suppressed under hypoxic conditions. Theoretical and experimental analyses revealed that GSH oxidation was driven by the reduction of Mn and the sacrificing of lattice oxygen, which generated oxygen vacancies and a rougher material surface. In vitro and in vivo 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.