Programmably Controllable Delivery of Metastable Ferrous Ions for Multiscale Dynamic Imaging Guided Photothermal Primed Chemodynamic Therapy

Abstract Metallomodulation cell death strategies are extensively investigated for antitumor therapy, such as cuproptosis, ferroptosis, and chemodynamic therapy (CDT). Undoubtedly, the accurate and specific elevation of metal ions levels in cancer cells is key to boosting their therapeutic index. Herein, a programmably controllable delivery system based on croconium dye (Croc)–ferrous ion (Fe²⁺) nanoprobes (CFNPs) is developed for multiscale dynamic imaging guided photothermal primed CDT. The Croc, with kinds of electron‐rich iron‐chelating groups, can form the Croc–Fe²⁺ complex with a precise stoichiometry of 1:1 to steadily maintain the valence state of Fe²⁺. The CFNPs can achieve pH‐responsive visualization and accurate Fe²⁺ release in cancerous tissues under the coactivation of “dual‐key” stimulation of “acidity and near‐infrared (NIR) light”. The acidic tumor microenvironment actuates NIR fluorescence/photoacoustic imaging and photothermal properties of CFNPs. Sequentially, under exogenous NIR light, the CFNPs enable in vivo accurate visualization of Croc–Fe²⁺ complex delivery for photothermal primed Fe²⁺ release, thus achieving CDT of tumors. By leveraging multiscale dynamic imaging technologies, the complicated spatiotemporal release of Fe²⁺ is sketched in a programmably controllable manner, and the domino effect of tumor pH level, photothermal effect, and CDT is also revealed, endowing customized feedback of the therapeutic panorama within the disease microenvironment.