Glutathione‐Responsive Cu Nanoplatform Enables Quantitative CEST MRI for Predicting Cuproptosis Therapeutic Response

ABSTRACT Accurate quantification of glutathione (GSH), a key regulator of intracellular redox homeostasis, and its correlation with the early therapeutic response to cuproptosis‐based treatment in animal models are crucial for developing effective glutathione‐depletion therapeutics, yet in vivo GSH quantification remains challenging. Here, we developed a GSH‐responsive Cu nanoplatform (Cu‐CDs) for early and noninvasive assessment of cuproptosis by exploiting the thiol chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) signal of glutathione. In vivo studies in 4T1 tumor‐bearing mice demonstrated that thiol CEST MRI enabled quantitative detection of GSH as low as 0.39 µmol/g in tumors (R 2 = 0.944). Notably, no correlation was observed between the levels of GSH and the MRI signals (R 2 = 0.302 or 0.117) from the exogenous analog, indicating that assessments using exogenous probes at a single time point were inaccurate. Remarkably, dynamic changes in the thiol CEST signals within only 8 h after administration of the Cu‐CDs strongly correlated with the tumor inhibition rate measured (R 2 = 0.993), enabling early prediction of the long‐term cuproptosis therapeutic efficacy. Thus, CEST MRI provides a non‐invasive and quantitative approach for monitoring GSH in vivo, with potential for assessing therapeutic agent accumulation and predicting early therapeutic response of GSH‐related therapies.