Enzyme Core Spherical Nucleic Acid That Enables Enhanced Cuproptosis and Antitumor Immune Response through Alleviating Tumor Hypoxia

• Published in: Journal of the American Chemical Society Vol. 146; no. 20; pp. 13805 - 13816
• Main Authors: Huang, Yuting, Liu, Xueliang, Zhu, Jiawei, Chen, Zhejie, Yu, Lu, Huang, Xin, Dong, Chuhuang, Li, Jiabei, Zhou, Huayuan, Yang, Yu, Tan, Weihong
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 22.05.2024
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Catalase - chemistry; Catalase - metabolism; Cell Line, Tumor; Copper - chemistry; Dendritic Cells - drug effects; Dendritic Cells - immunology; Humans; Immunogenic Cell Death - drug effects; Mice; Neoplasms - drug therapy; Neoplasms - immunology; Tumor Hypoxia - drug effects; Tumor Microenvironment - drug effects
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.3c14247

Cuproptosis, a copper-dependent cell death process, has been confirmed to further activate the immune response and mediate the immune resistance. However, hypoxic tumor microenvironment hampers cuproptosis sensitivity and suppresses the body’s antitumor immune response. Herein, we have successfully immobilized and functionalized catalase (CAT) with long single-stranded DNA containing polyvalent CpG sequences through rolling circle amplification (RCA) techniques, obtaining an enzyme-cored spherical nucleic acid nanoplatform (CAT-ecSNA-Cu) to deliver copper ions for cuproptosis. The presence of long-stranded DNA-protected CAT enhances mitochondrial respiration by catalyzing the conversion of H2O2 to O2, thereby sensitizing cuproptosis. Meanwhile, increased tumor oxygenation suppresses the expression of the hypoxia-inducible factor-1 (HIF-1) protein, resulting in the alleviation of the immunosuppressive tumor microenvironment. Of note, cuproptosis induces immunogenic cell death (ICD), which facilitates dendritic cell (DC) maturation and enhances antigen presentation through polyCpG-supported Toll-like receptor 9 (TLR9) activation. Furthermore, cuproptosis-induced PD-L1 upregulation in tumor cells complements checkpoint blockers (αPD-L1), enhancing antitumor immunity. The strategy of enhancing cuproptosis-mediated antitumor immune responses by alleviating hypoxia effectively promotes the activation and proliferation of effector T cells, ultimately leading to long-term immunity against cancer.