Novel FeF₂/Fe_1–xS Nanoreactor‐Mediated Mitochondrial Dysfunction via Oxidative Stress and Fluoride Ions Overloaded for Synergistic Chemodynamic Therapy and Photothermal Therapy

Abstract Selecting subcellular organelles as therapeutic targets have drawn great interest for cancer treatment. Herein, novel nanotheranostic agents FeF₂/Fe_1–xS nanorods modified by polyethylene glycol (FFSNRs‐PEG) are first synthesized for tumor microenvironments (TME) responsive magnetic resonance imaging (MRI) guided synergetic cancer therapy focused on the mitochondria. In TME, the Fe²⁺ and F⁻ ions released from FFSNRs‐PEG can make mitochondrial damage via the production of toxic ·OH through Fenton reaction and activation of caspase‐3, resulting in apoptosis and cell death. Taking advantage of the strong absorption of FFSNRs‐PEG in the second biowindow (1000–1700 nm), the photothermal effect boosts the efficiency of Fenton reaction to achieve synergetic chemodynamic therapy and photothermal therapy under near‐infrared light (1064 nm) irradiation. In addition, benefiting from the self‐oxidation effect, the FFSNRs‐PEG can serve as a novel TME‐responsive contrast agent for T₂‐weighted MRI. Overall, this work highlights an innovative “weapon” to realize TME‐responsive tumor diagnosis and synergetic therapies focused on the mitochondria.