Copper-based fluorinated MOFs for activatable multicolor 19F MRI and regulated cell death-promoting therapy of tumor

Fluorine-19 magnetic resonance imaging (MRI) is emerging as a promising multiplexed molecular imaging technique that is complement to traditional anatomical 1H MRI. Unfortunately, the further development and popularization of 19F MRI, especially multicolor 19F MRI, is substantially restricted by the limited types of imaging probes. In this study, we constructed a stimuli-responsive nanoagent (Cu-DFL) based on copper-based fluorinated metal-organic frameworks (MOFs) for tumor visualization via dual-color 19F MRI and cancer therapy by promoting regulated cell death (RCD). The degradation of this nanoagent in the presence excess glutathione (GSH) in tumor microenvironment (TME) results in the release of two fluorinated organic ligands with distinct 19F chemical shifts, which substantially strengthens 19F signals for dual-color 19F MRI of tumor. Meanwhile, Cu2+ ions are discharged and soon reduced to Cu+ ions by GSH, which causes significant cuproptosis by inducing the aggregation of dihydrolipoyl transacetylase (DLAT). The presence of Cu+ ions also facilitates the intracellular Fenton reaction, which leads to considerable oxidative stress and subsequent mitochondria-mediated apoptosis. The downregulation of GPX4 due to the depletion of GSH and the enhanced oxidative stress contribute to excess lipid peroxidation (LPO), resulting in significant ferroptosis. These different types of RCD triggered by Cu-DFL contribute to the annihilation of cancer cells and the ablation of tumor. These results illustrated the promising potential of our nanoagent for accurate tumor visualization via multi-color 19F MRI and effective cancer therapy by stimulating multiple types of RCD, further demonstrating the potentiality of fluorinated MOFs for biomedical applications. [Display omitted] •Copper-based fluorinated metal-organic frameworks (MOFs) can visualize tumor via stimuli-responsive dual-color 19F MRI.•The generation of Cu+ ions caused significant cuproptosis by inducing the aggregation of dihydrolipoyl transacetylase (DLAT).•The presence of Cu+ ions also led to mitochondria-mediated apoptosis.•The downregulation of GPX4 due to the depletion of GSH resulted in significant ferroptosis.