Fluorinated Core–Shell Metal–Organic Framework-Based Dual-Activated ¹⁹ F MRI Nanoprobes for In Vivo Visualization of the Tumor Microenvironment

In vivo simultaneous visualization of the dynamic changes in biomarkers within the tumor microenvironment (TME) is crucial for elucidating the mechanisms underlying tumor initiation and progression and providing pivotal insights for tumor management. Herein, we develop an acidosis- and inorganic phosphate-dual-responsive fluorinated core-shell nanoprobe (Zr@Zn-MOF) from corresponding metal ions and fluorinated ligands for visualizing the TME in vivo via multiplexed 19F magnetic resonance imaging (MRI). In normal tissues, the insignificant dual-channel 19F MRI signals of Zr@Zn-MOF could be ascribed to the close packing of 19F nuclei within Zr@Zn-MOF, which strengthens magnetic dipolar interactions. In contrast, activated by the low pH and high phosphate level of the TME, the core-shell nanoprobe undergoes rapid degradation to release fluorinated ligands, resulting in the intensification of dual-channel signals for multicolor 19F MRI. A series of imaging experiments validates the mechanism of this nanoprobe and illustrates its favorable performance of reassuring visualization of the TME with high penetration depth and low biological background. Our study demonstrates the promising potential of this nanoprobe for imaging-related tumor management and the success of our strategy that takes advantage of core-shell MOFs for the construction of multiple stimuli-responsive 19F MRI nanoprobes.