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 Fe 3+ and Fe 2+ 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 (H 2 S) for apoptotic cell death. The DATS depleted intracellular glutathione (GSH), which together with the produced H 2 S boosted ferroptosis. Ferroptosis and H 2 S 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.