Construction of Methotrexate-Loaded Bi₂S₃ Coated with Fe/Mn-Bimetallic Doped ZIF-8 Nanocomposites for Cancer Treatment Through the Synergistic Effects of Photothermal/Chemodynamic/Chemotherapy

A combination of therapeutic modalities in a single nanostructure is crucial for a successful cancer treatment. Synergistic photothermal therapy (PTT) can enhance the effects of chemodynamic therapy (CDT) and chemotherapy, which could intensify the therapeutic efficacy to induce cancer cell apoptosis. In this study, Fe and Mn on a zeolitic imidazolate framework (ZIF-8) (Fe/Mn-ZIF-8; FMZ) were synthesized through ion deposition. Furthermore, bismuth sulfide nanorods (Bi₂S₃ NRs; BS NRs) were synthesized via a hydrothermal process and coated onto FMZ to generate the core-shell structure of the Bi₂S₃@FMZ nanoparticles (B@FMZ). Next, methotrexate (MTX) was loaded effectively onto the porous surface of ZIF-8 to form the B@FMZ/MTX nanoparticles. The Fenton-like reaction catalyzes Fe²⁺/Mn²⁺ ions by decomposing H₂O₂ in the tumor microenvironment, resulting in the formation of toxic hydroxyl radicals (·OH), which promotes the CDT effect of killing cancer cells. Furthermore, under 808 nm laser irradiation, these B@FMZ nanoparticles showed a strong PTT effect, owing to the presence of intense BS NRs as a photothermal agent. The B@FMZ nanoparticles exhibited a prominent drug release efficiency of 87.25% at pH 5.5 under near-infrared laser irradiation due to the PTT effect can promote the drug delivery performance. The B@FMZ nanoparticles were subjected to dual-modal imaging, guided magnetic resonance imaging, and X-ray computed tomography imaging. Both <i>in vitro</i> and <i>in vivo</i> results suggested that the B@FMZ/MTX nanoparticles exhibited enhanced antitumor effects through the combined therapeutic effects of PTT, CDT, and chemotherapy. Therefore, these nanoparticles exhibit good biocompatibility and are promising candidates for cancer treatment.