Relaxation Suppressed Exchange Tuning MRI Integrated with Manganese-Based Nanozyme Probes for Ferroptosis Induction and GPX4 Monitoring

  • ACS Appl Bio Mater. 2026 May 4;9(9):4297-4313. doi: 10.1021/acsabm.6c00454.
Xinyi Ding  1  2 ,  Yi Zhu  2 ,  Jingyan Fang  3 ,  Jiali Deng  2 ,  Jingyi Wang  4 ,  Zhu Mei  5 ,  Xiance Zhao  6 ,  Hongwei Lu  3 ,  An Chen  2 ,  Zhongling Wang  2
Affiliations
  • 1. Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.
  • 2. Department of Radiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
  • 3. Department of Biomedical Engineering, College of Engineering, Shantou University, Shantou 515063, China.
  • 4. School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.
  • 5. Shanghai Key Laboratory of Pancreatic Diseases, Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
  • 6. Philips Healthcare, Shanghai 200072, China.
PMID: 41979062 DOI: 10.1021/acsabm.6c00454
Abstract

Ferroptosis has emerged as a viable approach to enhance therapeutic efficacy in triple-negative breast Cancer (TNBC), making monitoring essential for prognostic evaluation. However, conventional MR imaging cannot characterize ferroptosis-related biomarkers. Herein, we propose a Relaxation Suppressed Exchange Tuning (ReSET) MRI strategy for Ferroptosis modulation and monitoring, which relies on T1 relaxation and chemical exchange saturation transfer (CEST). ReSET was achieved by a tumor-microenvironment-responsive nanoprobe (SiO2@FUDR@MnO2, SiFM), consisting of a mesoporous silica core loaded with chemotherapeutic floxuridine and the MnO2 shell with nanozyme activities. This structure promotes robust ROS generation, which induces lipid peroxidation and ultimately facilitates chemodynamic therapy (CDT)-sensitized Ferroptosis. Notably, ReSET takes advantage of the tumor-responsive release of Mn2+ from SiFM, which shortens T1 relaxation and suppresses the saturation transfer efficiency between water and exchangeable endogenous protons reducing magnetization transfer ratio asymmetry (MTRasym). The inverse correlation between the T1 intensity and MTRasym provides a sensitive and specific indicator for visualizing Glutathione Peroxidase 4 (GPX4) expression, thereby enabling cross-modal monitoring of Ferroptosis. Meanwhile, we revealed that the ReSET strategy enables sensitive detection of small lesions in liver micrometastasis models. Overall, we establish a ReSET MRI-guided strategy using a manganese-based nanoplatform, which represents a promising ferroptosis-related theranostic approach for TNBC.

Keywords
chemical exchange saturation transfer (CEST); ferroptosis; glutathione peroxidase4; manganese-based nanozyme probes; relaxation suppressed exchange tuning (ReSET) MRI.
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