Biomimetic nanoplatform with multienzyme cascade activity boosting ROS generation and immune activation feedback for tumor therapy

Nanocatalytic medicine has emerged as a promising strategy for tumor therapy, utilizing nanozymes to generate cytotoxic reactive oxygen species (ROS). Despite significant progress, challenges persist, including low catalytic efficiency and inadequate tumor targeting. Herein, we report a tumor cell membrane coated biomimetic nanozyme platform (CMNP) containing manganese dioxide nanoparticles (MnO 2 @BSA), nano-realgar (NR), and doxorubicin (DOX). This nanoplatform targets tumors via biomimetic properties. In the tumor, MnO 2 alleviates hypoxia by catalytically decomposing H 2 O 2 to produce O 2 , thereby enhancing the enzymatic activity of NR. As the nanocrystalline form of a traditional Chinese medicine, NR exhibits glutathione oxidase (GSHOx)- and L-cysteine oxidase (LCO)-like activities, generating substantial cytotoxic ROS. These cascade catalysis-enhanced ROS not only induce tumor cell apoptosis but also activate immune responses in the tumor microenvironment. Furthermore, released DOX and Mn 2+ ions recruit tumor-killing immune cells by inducing the immunogenic cell death (ICD) of tumor cells and activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, respectively. The tumor suppression stems from a positive feedback regulation driven by ROS generation and immune activation. Our study proposes a versatile nanoplatform that offers a two-pronged treatment strategy. We report a biomimetic nanozyme platform (CMNP) containing manganese dioxide nanoparticles (MnO 2 @BSA), nano-realgar (NR), and doxorubicin (DOX) coated with tumor cell membrane. The tumor suppressive effects with CMNP treatment are amplified via synergism between the nanocatalytic cascade effect and the two-pronged treatment strategy. CMNP offers a novel and valuable approach for treating tumor. • The Glutathione oxidase- and L-cysteine oxidase-like activities of nano realgar are first reported. • The cascade catalytic effect of multiple nanoenzymes promotes tumor treatment. • The positive feedback regulation of ‘oxidative stress-ferroptosis-immune activation’.