Engineering Multienzyme‐Mimicking Covalent Organic Frameworks as Pyroptosis Inducers for Boosting Antitumor Immunity
Liang Zhang, Qi‐Chao Yang, Shuo Wang, Yao Xiao, Shu‐Cheng Wan, Hexiang Deng, Zhi‐Jun Sun
Abstract
Abstract The engineering of a series of multienzyme‐mimicking covalent organic frameworks (COFs), COF‐909‐Cu, COF‐909‐Fe, and COF‐909‐Ni, as pyroptosis inducers, remodeling the tumor microenvironment to boost cancer immunotherapy, is reported. Mechanistic studies reveal that these COFs can serve as hydrogen peroxide (H 2 O 2 ) homeostasis disruptors to elevate intracellular H 2 O 2 levels, and they not only exhibit excellent superoxide dismutase (SOD)‐mimicking activity and convert superoxide radicals (O 2 •− ) to H 2 O 2 to facilitate H 2 O 2 generation, but also possess outstanding glutathione peroxidase (GPx)‐mimicking activity and deplete glutathione (GSH) to alleviate the scavenging of H 2 O 2 . Meanwhile, the outstanding photothermal therapy properties of these COFs can accelerate the Fenton‐like ionization process to facilitate their chemodynamic therapy efficiency. One member, COF‐909‐Cu, can robustly induce gasdermin E (GSDME)‐dependent pyroptosis and remodel the tumor microenvironment to trigger durable antitumor immunity, thus promoting the response rate of αPD‐1 checkpoint blockade and successfully restraining tumor metastasis and recurrence.