A cascade nanoreactor with ROS storms activation for amplified multimodal synergistic cancer therapy

The complexity, variability, and heterogeneity of the tumor microenvironment make it impossible for monotherapy to achieve the desired therapeutic effect. The utilization of nanoreactor-based multimodal synergistic therapy represents a highly promising approach. Consequently, we utilized metal coordination-constructed metal-phenolic networks (MPNs) to encapsulate glucose oxidase (GOx), which then co-assembled with indocyanine green (ICG), ultimately forming a cascade nanoreactor (GOx@TF-ICG NPs) that exhibits a multimodal synergistic therapeutic effect. As a simple and efficient nanoreactor, it initiates a cascade reaction by GOx and achieves multimodal synergistic anti-tumor. After entering the tumor microenvironment, the nanoreactor catalyzes glucose to produce hydrogen peroxide (H₂O₂), initiating a cascade that triggers a reactive oxygen species (ROS) storm, enhancing chemodynamic therapy (CDT) and photodynamic therapy (PDT), ultimately inducing ferroptosis. The photothermal effect directly initiated by the coordination structure of MPNs and ICG, together with the down-regulation of heat shock proteins, jointly strengthens the photothermal therapy (PTT) effect. The experimental results show that the nanoreactor can also induce tumor cell apoptosis by decreasing the mitochondrial membrane potential. Therefore, the nanoreactor integrates starvation therapy (ST)/PDT/PTT/ferroptosis and has a significant anti-tumor effect. This strategy provides ideas and theoretical guidance for combination therapy in improving the clinical treatment effect of tumors.