Real-Time Imaging Guided MTH1 Inhibition-Augmented Ferroptosis Therapy by Engineered Nanoinducers

Conventional ferroptosis inducers often suffer from off-target iron accumulation and insufficient reactive oxygen species (ROS) amplification in tumors, as well as a lack of imaging guidance, and their efficacy is further counteracted by MutT homolog 1 (MTH1)-mediated sanitization of oxidative DNA damage, collectively limiting therapeutic precision. Here, to circumvent these barriers, we report an engineered nanoinducer integrating ferric ions and a phosphonate-containing hemi-cyanine scaffold for real-time imaging-guided, MTH1 inhibition-augmented ferroptosis. This nanoinducer exhibits tumor-specific accumulation and acid-triggered dissociation, releasing ferric ions (ferroptosis inducer) and the MTH1 inhibitor TH588. The release kinetics are visualized in real-time via fluorescence imaging using a phosphatase-cleavable hemi-cyanine probe, enabling dynamic therapy monitoring. Mechanistically, ferric ions generate hydroxyl radicals to drive lipid peroxidation and nucleotide oxidation, inducing ferroptosis and DNA mispairing, while TH588 suppresses MTH1 activity, blocking ROS-induced DNA damage repair and amplifying ROS cytotoxicity. This synergistic strategy significantly enhances antitumor efficacy, suppresses metastasis, and exhibits minimal off-target toxicity.