Fluorine Meets Amine: Reducing Microenvironment-Induced Amino-Activatable Nanoprobes for ¹⁹F-Magnetic Resonance Imaging of Biothiols

¹⁹F-magnetic resonance imaging (MRI) is of great significance for noninvasive imaging and detection of various diseases. However, the main obstacle in the application of ¹⁹F-MRI agents stems from the unmet signal sensitivity due to the poor water solubility and restricted mobility of segments with high number of fluorine atoms. Herein, we report a kind of intracellular reducing microenvironment-induced amino-activatable ¹⁹F-MRI nanoprobe, which can be used for specific imaging of biothiols. In principle, the nanoprobe has an initial architecture of hydrophobic core, where the trifluoromethyl-containing segments are compactly packed and ¹⁹F NMR/MRI signals are quenched ("OFF" state). Upon encountering sulfydryl, the strong electron-withdrawing 2,4-dinitrobenzenesulfonyl groups are excised to recover secondary amino groups, whose pK_a is proved to be 7.21. As a consequence, the molecular weight loss of the hydrophobic segment and the protonation of amino groups induce significant disturbance of hydrophilic/hydrophobic balance, leading to the disassembly of the nanoprobes and regain of spin-spin relaxation and ¹⁹F NMR/MRI signals ("ON" state, T₂ up to 296 ± 5.3 ms). This nanoprobe shows high sensitivity and selectivity to biothiols, enabling intracellular and intratumoral imaging of glutathione. Our study not only provides a new nanoprobe candidate for biothiols imaging in vivo but also a promising strategy for the molecular design of real water-soluble and highly sensitive ¹⁹F-MRI nanoprobes.