A multi-functional integrated nanoplatform based on a tumor microenvironment-responsive PtAu/MnO2 cascade nanoreactor with multi-enzymatic activities for multimodal synergistic tumor therapy

The utilization or improvement of tumor microenvironment (TME) has become a breakthrough in emerging oncology therapies. To address the limited therapeutic efficacy of single modality, a multi-functional integrated nanoplatform based on a TME-responsive PtAu/MnO₂ cascade nanoreactor with multi-enzymatic activities was developed for multimodal synergistic tumor therapy. Benefiting from the slightly acidic environment and high-level glutathione (GSH) in TME, PtAu/MnO₂ cascade nanoreactor consumed GSH, followed by the reductive generation of manganese ion (Mn²⁺) and the release of PtAu nanoparticles (NPs). Then, the multimodal synergistic tumor therapy was activated as follows. First, GSH depletion inhibited the activity of glutathione peroxidase 4 and led to the accumulation of lipid peroxidation, thereby inducing tumor cell ferroptosis. Second, PtAu NPs exhibited catalase-like, glucose oxidase-like and nicotinamide adenine dinucleotide (NADH) oxidase-like activities, which generated oxygen for the cascade reaction to alleviate hypoxia and further depleted glucose, NADH and adenosine triphosphate, leading to the inhibition of tumor cell proliferation via starvation therapy. Third, the production of reactive oxygen species by the oxidase- and peroxidase-like activities of PtAu NPs and the Fenton-like reaction of Mn²⁺ simultaneously induced tumor cell apoptosis via chemodynamic therapy. Briefly, the in vitro and in vivo results confirmed that the multi-functional integrated nanoplatform based on a PtAu/MnO₂ cascade nanoreactor with five nanozyme activities demonstrated outstanding biocompatibility and greater inhibition of tumor growth via synergistic ferroptosis/starvation therapy/apoptosis.