Self-assembled copper chlorogenic acid nanoparticles: Inducing pyroptosis and cuproptosis to activate antitumor immunity

Abstract

Currently, the tumor treatment faces many challenges. Although chemotherapy is the most effective and economical choice, most chemotherapy drugs lack tumor specificity, have low bioavailability, and face many obstacles in clinical application. Significantly, the tumor immunosuppressive microenvironment (TIME) and low immunogenicity in solid tumors also seriously affect the clinical effect of tumor therapy. Here, metal-phenolic network nanoparticles self-assembled by copper-coordinated natural drug chlorogenic acid (ChA) (ChA-Cu NPs) are designed to amplify cell immunogenic death mediated by cuproptosis and pyroptosis for antitumor immunotherapy. Specifically, the synthesized ChA-Cu NPs can disintegrate and release Cu²⁺ and the polyphenol drug ChA in the tumor microenvironment, realizing the combined chemotherapy/chemodynamic kinetics in the treatment of tumors. Importantly, the release of Cu²⁺ and ChA can drive the cascade reaction, which can disturb redox homeostasis by producing reactive oxygen species (ROS) and depleting GSH, and induce pyroptosis and make tumor cells more sensitive to cuproptosis. Furthermore, pyroptosis and cuproptosis can evoke immunogenic cell death (ICD) and release damage-associated molecular patterns (DAMPs), stimulating dendritic cells (DCs) to mature and activate CD8⁺ T cells. It is encouraging that ChA-Cu NPs can reprogram TIME to achieve significant tumor growth inhibition.