Augmenting Immunotherapy via Bioinspired MOF-based Ros Homeostasis Disruptor with Nanozyme-Cascade Reaction.

Despite its remarkable clinical breakthroughs, immune checkpoint blockade (ICB) therapy remains limited by the insufficient immune response in the "cold" tumor. Nanozyme-based antitumor catalysis is associated with precise immune activation in the tumor microenvironment (TME). In this study, a cascade-augmented nanoimmunomodulator (CMZM) with multienzyme-like activities, which includes superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and glutathione oxidase (GSHOx), that dissociates under an acidic and abundant GSH TME, is proposed for multimodal imaging-guided chemodynamic therapy (CDT)/photodynamic therapy (PDT) enhanced immunotherapy. Vigorous multienzyme-like activities can not only produce O 2 to alleviate hypoxia and promote the polarization of M2 to M1 macrophages but also generate ROS (•OH and 1 O 2 ) and deplete GSH in the TME to expose necrotic cell fragments and reverse immunosuppressive TME by eliciting the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes in tumors. Therefore, inhibitory effects on both primary and distant tumors were achieved through synergy with an α-PD-L1 blocking antibody. This cascade multienzyme-based nanoplatform provides a smart strategy for highly efficient ICB immunotherapy against "cold" tumors by revising immunosuppressive TME. This article is protected by copyright. All rights reserved.