Biomineralized manganese-based cascade nanosystem for augmented combinational therapy of oral cancer and dual-modal imaging-guided diagnosis

• Manganese-based cascade nanosystem (p-GMI) is made by biomineralization. • p-GMI is formed by glucose oxidase and biopolymer ε-poly-L-lysine (EPL) as template. • p-GMI shows fluorescence imaging/magnetic resonance imaging-guided therapeutic uses. • p-GMI exhibits triple-enzyme activities enabling multimodal therapy of oral cancer. Due to the spatiotemporal specificity and high efficacy, tumor microenvironment (TME)-responsive nanozyme catalytic therapy has attracted considerable attentions. Nevertheless, it remained challenging to remodel TME for improving therapeutic benefits. Here, a TME-responsive nanozyme termed p-GOx-MnO 2 -ICG (p-GMI) was synthesized via biomimetic mineralization using ε-poly-L-lysine (EPL) as the template. The obtained p-GMI comprised glucose oxidase (GOx), MnO 2 nanoparticles, and photosensitizer indocyanine green (ICG), which exhibited prominent triple-enzyme activities (glucose oxidase, catalase-like, and peroxidase-like) enabling multimodal therapy. Specifically, starvation therapy (ST) was initiated through glutathione peroxidase-mediated glucose depletion. The released Mn 2+ in TME utilized the produced H 2 O 2 and gluconic acid to initiate Fenton-like reaction, enhancing chemodynamic therapy (CDT) efficacy. Meanwhile, the generated O 2 by catalase-like nanozyme can not only activate GOx but serve as the photodynamic therapy (PDT) substrate, leading to synergistically improved ST and PDT outcomes. Both in vitro and in vivo experiments indicated p-GMI nanozyme enabled fluorescence imaging/magnetic resonance imaging-guided ST/CDT/PDT combinational therapy, while also exhibiting favorable biosafety in the CAL-27 xenograft mouse model. Therefore, the built TME-responsive and dual-modal imaging guided p-GMI nanozymes as integrated cascade nanosystem held potentials in dealing with oral cancer.