A hollow mesoporous manganese oxide based multifunctional nanozyme with self-propelled nanomotor behavior and direct copper binding ability for synergistic therapy of glioblastoma with hypoxia alleviation

A shape templating hydrothermal oxidation protocol was proposed for the synthesis of hollow, mesoporous manganese oxide nanospheres (H-MnOx NSs). H-MnOx NSs exhibited a photothermal conversion behavior and acted a multifunctional nanozyme behavior with peroxidase (POD)-like, oxidase (OD)-like and catalase (CAT)-like activities. CAT-like activity which was far superior with respect to the similar agents allowed fast oxygenation of tumor microenvironment for hypoxia relief and the enhancement of ROS production. A self-propelled nanomotor behavior was also observed due to the oxygen evolution from H2O2. Cu(II) loaded form of H-MnOx NSs (H-MnOx@Cu NSs) were obtained by direct interaction with Cu (II) cations. Effective generation of hydroxyl (center dot OH) and superoxide anion (O-2(-center dot)) radicals by H-MnOx@Cu NSs were demonstrated by Electron Spin Resonance (ESR) spectroscopy. POD-like activity, center dot OH generation rate and GSH depletion ability markedly increased by the attachment of Cu(II) cations onto H-MnOx NSs. Chlorine e6 (Ce6) loaded form of H-MnOx@Cu NSs (H-MnOx@Cu@Ce6 NSs) was evaluated as a synergistic therapy agent capable of generating O-1(2), SOH and O-2(-center dot) radicals, and having photothermal, chemodynamic and photodynamic functions. T98G glioblastoma cell deaths higher than 90 % were achieved by the enhanced interaction of H-MnOx@Cu@Ce6 NSs with the cells induced by nanomotor function, the temperature elevation stemmed from photothermal conversion, and the enhancement of chemodynamic and photodynamic functions by both temperature elevation and O-2 evolution. The effectiveness of H-MnOx@Cu@Ce-6 NSs for the inhibition of proliferation and the migration of T98G cells was also demonstrated by scratch and TUNEL assays.