Tri-Stimulus-Responsive Hollow Mesoporous MnO₂ Nanocarriers for Magnetic-Resonance-Imaging-Guided Synergistic Starvation/Photodynamic Therapy of Breast Cancer

Hypoxia, a distinct feature of breast cancer, can affect the effectiveness of breast cancer therapy. To alleviate the hypoxic state of the tumor microenvironment and achieve synergistic starvation-photodynamic therapy (PDT), we have developed a simple and effective multifunctional nanoplatform. Spherical silica (SiO 2 ) serves as a template for the synthesis of hollow mesoporous MnO 2 (H-MnO 2 ) nanoparticles, which act as the carriers of chlorin e6 (Ce6) and glucose oxidase (GOx). Subsequently, the particles are modified with the surfactant Pluronic F-127, leading to the formation of a H-MnO 2 /Ce6/GOx/F-127 (MCGF) nanoplatform. During tumor treatment, pH/glutathione/H 2 O 2 -responsive MCGF allows the controlled release of encapsulated Ce6 and GOx, avoiding pre-exposure to body fluids. Upon release, GOx oxidizes endogenous glucose to generate H 2 O 2 and gluconic acid. The catalase-like H-MnO 2 reacts with the endogenous and glucose-oxidation-generated H 2 O 2 to produce O 2 . Reinforcement between these catalytic reactions promotes the O 2 -dependent Ce6-mediated PDT and GOx-induced starvation therapy. Moreover, T1-weighted magnetic resonance imaging (MRI) of Mn 2+, which is produced by H-MnO 2 degradation, allows for real-time tumor therapy monitoring. Both in vitro and in vivo experiments demonstrate that the MCGF nanoplatform allows MRI monitoring and achieves efficient starvation/PDT effects for synergistic breast cancer treatment. We believe that our findings will contribute to the development of nanotheranostic platforms for breast cancer starvation/PDT.