pH-responsive Fe/Mn-doped mesoporous silica nanozymes for synergistic chemophotothermal therapy in breast cancer via hypoxia alleviation and controlled drug release

Nanozyme-based nanostructures hold great promise for breast cancer therapy by enabling controlled drug delivery, modulating the tumor microenvironment, and integrating with auxiliary treatments. In this study, we developed pH-sensitive mesoporous silica nanoparticles doped with iron and manganese and loaded with doxorubicin (mSiO₂-Fe/Mn@DOX). The resulting hybrid nanozymes (∼40.9 nm) exhibited a high drug loading capacity (83.9%) and pH-triggered release of Doxorubicin (DOX), accompanied by concurrent Fe (31.3%) and Mn (39.9%) ion release under acidic conditions. Catalytic assays demonstrated effective oxygen generation (14.2 mg L -1 ), alleviating tumor hypoxia and contributing to synergistic therapeutic outcomes. In MD anderson – metastatic breast – 231 (MDA-MB-231) breast cancer cells, combining mSiO₂-Fe/Mn@DOX with photothermal therapy (PTT) enhanced anticancer efficacy, reducing the effective DOX dose from 2.16 to 1.08 μg mL -1 while minimizing cytotoxicity to normal cells. In 3D tumor spheroids, this combination treatment significantly induced apoptosis, evidenced by upregulation of tumor necrosis factor alpha (TNF-α), caspase-9 (CASP9), caspase-7 (CASP7), caspase-3 (CASP3). Overall, these findings demonstrate a multifunctional nanozyme platform that couples pH-responsive drug release with PTT to optimize therapeutic performance and reduce off-target effects.