Integration of Fe(III)-Chelated Polydopamine and Diallyl Trisulfide for Boosting Ferroptosis to Reverse Multidrug Resistance and Inducing Synergistic Tumor Nanotherapy

Multidrug resistance (MDR) has long been a fundamental obstacle in tumor chemotherapy. MDR is often associated with overexpression of an adenosine triphosphate (ATP)-binding cassette transporter in resistant cancer cells, which is highly ATP-dependent. Therefore, reversing MDR by down-regulated ATP expression is a promising strategy. This study developed a redox-regulating nanotherapeutic for boosting ferroptosis, reversing MDR, and inducing synergistic tumor therapy. Fe(III)-chelated polydopamine (Fe-PDA) is the key to the design of such a nanotherapeutic, and laser irradiation can speed up the electron transfer between Fe3+ and Fe2+ and the production of a hydroxyl radical (•OH). Coating a layer of Fe-PDA on the surface of mesoporous silica (MSN)-encapsulated diallyl trisulfide (DATS), and the doxorubicin (DOX) was loaded on the surface of Fe-PDA. Upon triggering, the nanotherapeutic (DATS@MSN@Fe-PDA/DOX, DMFPD) produced a photothermal hydroxyl radical (•OH) and hydrogen sulfide (H2S) for apoptotic cell death. The DATS depleted intracellular glutathione (GSH), which together with the produced H2S boosted ferroptosis. Ferroptosis and H2S effectively caused mitochondrial dysfunction, thereby suppressing the ATP expression. The interactive cell death and chemotherapy sensitization were further demonstrated in a 4T1 tumor-bearing mouse model with a high level of biosafety. This study provides a promising strategy for clinical cancer theragnostics.