Relaxation Suppressed Exchange Tuning MRI Integrated with Manganese-Based Nanozyme Probes for Ferroptosis Induction...

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 (MTR_asym). The inverse correlation between the T1 intensity and MTR_asym 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.