An Enzyme-Triggered Self-Immobilizing Dual-Modal Probe for Precision Imaging and Sustained Gas Therapy of Early-Stage MASH

The clinical management of metabolic dysfunction-associated steatohepatitis (MASH) is hindered by the lack of noninvasive molecular diagnostics and effective targeted therapies. Although hydrogen sulfide (H2S) can ameliorate MASH via antioxidant and anti-inflammatory effects, conventional H2S donors suffer from uncontrolled burst release and rapid in vivo clearance. Here, we report AzoR-Cy-Gd, a magnetic resonance imaging (MRI)/fluorescence imaging (FLI)-guided H2S theranostic platform for early diagnosis, severity assessment, and visualized intervention of MASH. This hypoxia-responsive theranostic probe, featuring a reductively cleavable azo linkage, integrates a near-infrared cyanine fluorophore, a Gd-DO3A MRI contrast unit, and a carbonyl sulfide (COS)/H2S-releasing module. In MASH lesions, hypoxia-associated reductive activation induces cleavage of the azo bond, which subsequently triggers a self-immolative cascade, generating quinone methide (QM) for in situ protein anchoring and releasing COS for carbonic anhydrase-mediated H2S production. This synchronized activation restores intramolecular charge transfer, producing a 50-fold fluorescence enhancement and increasing relaxivity (r1) from 8.9 to 14.1 mM−1 s−1 while prolonging lesion retention. In a methionine/choline-deficient diet-induced mouse model, AzoR-Cy-Gd sensitively visualized hepatic pathogenesis and tracked disease progression from 4 to 8 weeks. Moreover, localized H2S release effectively suppressed inflammation, reduced lipid accumulation, and restored liver architecture and function. Overall, AzoR-Cy-Gd establishes a self-reporting “see-and-treat” strategy for precision MASH theranostics.