Virus‐Like Particle‐Induced cGAS‐STING Activation and AIM2 Inflammasome‐Mediated Pyroptosis for Robust Cancer Immunotherapy

cGAS‐STING‐mediated DNA sensing is demonstrated to be critical for launching antitumor immunity. However, DNA‐based cGAS‐STING agonists are rarely reported owing to low cell permeability, poor biostability and, especially, limited length of exogenous DNA. Here, we present a virus‐like particle which...

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Published in:Angewandte Chemie International Edition 2023-06, Vol.62 (24), p.e202303010-n/a
Main Authors: Xu, Xinyu, Fan, Huanhuan, Yang, Ying, Yao, Shankun, Yu, Wenhao, Guo, Zijian, Tan, Weihong
Format: Article
Language:English
Subjects:
AIM2 Inflammasome
Antitumor Immunotherapy
Biocompatibility
Biomedical materials
Cancer
Cancer immunotherapy
Cell permeability
cGAS-STING
Condensates
Deoxyribonucleic acid
DNA
DNA structure
DNA-Binding Proteins
Humans
Immunity
Immunogenicity
Immunotherapy
Inflammasomes
Inflammation
Liquid phases
Liquid-Liquid Phase Condensation
Neoplasms - therapy
Nucleotidyltransferases
Pyroptosis
Robustness
Self-assembly
Viruses
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Summary:cGAS‐STING‐mediated DNA sensing is demonstrated to be critical for launching antitumor immunity. However, DNA‐based cGAS‐STING agonists are rarely reported owing to low cell permeability, poor biostability and, especially, limited length of exogenous DNA. Here, we present a virus‐like particle which is self‐assembled from long DNA building blocks generated through rolling‐circle amplification (RCA) and covered with cationic liposomes. Based on long and densely packed DNA structure, it could efficiently induce liquid phase condensation of cGAS and activate STING signaling to produce inflammatory cytokines. Moreover, this virus‐like particle could also trigger the formation of AIM2 inflammasome to induce gasdermin D‐mediated pyroptosis, boosting antitumor immunity. Thus, this study provides a simple and robust strategy for cancer immunotherapy for clinical application. This is the first study to report the intrinsic immunogenicity of RCA products, thus facilitating their biomedical applications. We present a virus‐like particle loaded with densely packed DNA and covered with cationic liposomes. It not only induces liquid phase condensation of cGAS and activates STING signaling to produce inflammatory cytokines, but it also triggers the formation of AIM2 inflammasome and induces gasdermin D‐mediated pyroptosis to boost antitumor immunity, thus realizing efficient immunotherapy and tumor growth inhibition.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202303010