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

Metallo-modulation cell death strategies have been extensively investigated for antitumor therapy, such as cuproptosis, ferroptosis, chemodynamic therapy (CDT), etc. Undoubtedly, the accurate and specific elevation of metal ions levels in cancer cells is key to boosting the therapeutic index of these strategies. Herein, a programmably controllable delivery system is developed based on croconium dye (Croc)-ferrous ion (Fe 2+ ) nanoprobes (denoted as CFNPs) for multiscale dynamic imaging guided photothermal primed CDT. The Croc with kinds of electron-rich iron-chelating groups can form the Croc-Fe 2+ complex with a precise stoichiometry of 1:1 to steadily maintain the valence state of Fe 2+ . The CFNPs could achieve pH-responsive visualization of cancerous tissues, and accurate release of Fe 2+ in tumor 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 the in vivo accurate visualization of Croc-Fe 2+ complex delivery for photothermal primed Fe 2+ release, thus achieving CDT of tumors. By leveraging multiscale dynamic imaging technologies, we not only sketch the complicated spatiotemporal release of Fe 2+ in a programmably controllable manner, but also reveal the domino effect of tumor pH level, photothermal effect, and CDT, endowing the customized feedback of therapeutic panorama within disease microenvironment. This article is protected by copyright. All rights reserved.