Integration of Fe(III)-Chelated\nPolydopamine and Diallyl\nTrisulfide for Boosting Ferroptosis to Reverse Multidrug Resistance\nand Inducing Synergistic Tumor Nanotherapy

Multidrug resistance (MDR) has long been a fundamental\nobstacle\nin tumor chemotherapy. MDR is often associated with overexpression\nof an adenosine triphosphate (ATP)-binding cassette transporter in\nresistant cancer cells, which is highly ATP-dependent. Therefore,\nreversing MDR by down-regulated ATP expression is a promising strategy.\nThis study developed a redox-regulating nanotherapeutic for boosting\nferroptosis, reversing MDR, and inducing synergistic tumor therapy.\nFe(III)-chelated polydopamine (Fe-PDA) is the key to the design of\nsuch a nanotherapeutic, and laser irradiation can speed up the electron\ntransfer between Fe<sup>3+</sup> and Fe<sup>2+</sup> and the production\nof a hydroxyl radical (<sup>•</sup>OH). Coating a layer of\nFe-PDA on the surface of mesoporous silica (MSN)-encapsulated diallyl\ntrisulfide (DATS), and the doxorubicin (DOX) was loaded on the surface\nof Fe-PDA. Upon triggering, the nanotherapeutic (DATS@MSN@Fe-PDA/DOX,\nDMFPD) produced a photothermal hydroxyl radical (<sup>•</sup>OH) and hydrogen sulfide (H<sub>2</sub>S) for apoptotic cell death.\nThe DATS depleted intracellular glutathione (GSH), which together\nwith the produced H<sub>2</sub>S boosted ferroptosis. Ferroptosis\nand H<sub>2</sub>S effectively caused mitochondrial dysfunction, \nthereby suppressing the ATP expression. The interactive cell death\nand chemotherapy sensitization were further demonstrated in a 4T1\ntumor-bearing mouse model with a high level of biosafety. This study\nprovides a promising strategy for clinical cancer theragnostics.