Tumor microenvironment self-regulation: Bimetallic metal nanozyme-derived multifunctional nanodrug for optimizable cascade catalytic reaction-synergetic anti-tumor theranostics

• A multifunctional FeCu-GOx PNzyme was easily synthesized by a surfactant-free aqueous polymerization and coordination process. • Tumor microenvironment activated cascade catalytic reaction for enhanced oxidative stress. • FeCu-GOx PNzyme-MTO achieved multimodal imagings-guided photothermal-enhanced chemodynamic therapy and chemotherapy. The tumor microenvironment (TME) responsive multimodal theranostic nanoplatforms have attracted great attentions for precision medicine. To design well-defined cascade catalytic therapy and achieve the synergistic effect of different components in a nanoplatform, herein a spindle-shaped nanodrug termed as FeCu-GOx PNzyme-MTO was constructed by in-situ growth of bimetallic metal nanozyme (FeCu PNzyme), and simultaneous encapsulation of glucose oxidase (GOx) as well as fluorescent and chemotherapeutic mitoxanthrone (MTO). Interestingly, the obtained FeCu-GOx PNzyme is able to efficiently upregulate endogenous H 2 O 2 level and down-regulate acidity via inducing the catalytic decomposition of intratumoral glucose to gluconic acid and H 2 O 2 in TME, which is benefit to the cascade catalytic reactions for chemodynamic therapy (CDT). After efficient loading of MTO, such intelligent nanozyme triggers reactive oxygen species (ROS) generation in situ with tumor stimuli, self-augment ROS level upon intrinsic photothermal-conversion efficiency (53.05%) and glutathione (GSH) depletion, and specifically TME-responsive release of MTO to achieve high chemotherapeutic efficacy and biosafety. Both in vitro cellular assays and in vivo tumor-xenograft experiments proved that the tumor-specific cytotoxicity, biodegradability and potent antitumor efficiency of nanodrug, with co-contributions from highly cytotoxic ROS generated and precise drug delivery within tumors. This work thus presents the friendly construction of biocompatible FeCu-GOx PNzyme-MTO as effective nanodrug to provided a promising strategy for a new perspective on effective tumor therapy.