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 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.

Automated summary

By self-assembling virus-like particles with long DNA building blocks generated through rolling-circle amplification and covered with cationic liposomes, cGAS liquid phase condensation and STING signaling activation can be efficiently induced, leading to the production of inflammatory cytokines and boosting antitumor immunity. Additionally, these virus-like particles can also trigger the formation of AIM2 inflammasome and induce gasdermin D-mediated pyroptosis, further enhancing antitumor immunity. Thus, this study provides a simple and robust strategy for cancer immunotherapy for clinical application.