Abstract
Pyroptosis plays a crucial role in immune defense against infections and endogenous threats by eliminating harmful cells and modulating the immune response through inflammation. However, the natural activation of pyroptosis involves intricate signaling pathways, posing significant challenges for its artificial manipulation in research and therapies. Here, we present DAMAGE (Death Manipulation Gene), an innovative system that integrates gasdermins within the type III-E CRISPR framework, enabling the specific recognition of target RNA (tgRNA) and triggering pyroptosis. This mechanism allows DAMAGE to selectively identify and eliminate virus-infected, cancerous, and senescent cells, all of which exhibit altered RNA transcriptomes. Additionally, DAMAGE exhibits considerable promise as a platform for mRNA-LNP therapy. Our study highlights the potential of this CRISPR-based system in the controllable induction of pyroptosis, offering an innovative therapeutic strategy for treating RNA-heterogeneous diseases.
Data availability
Data supporting the findings of this study are available within the paper and its supplementary information files. Source data are provided with this paper.
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Acknowledgements
We gratefully acknowledge Professor Zheng Hu from Wuhan University School of Medicine, Wuhan, China for the generous gift of HeLa and C33-A cells, and the original plasmids of HPV16-E6/E7 and HPV18-E6/E7, which were used for further modification. This work was supported by grants from the National Key R&D Program of China (2023YFC2307800), the National Natural Science Foundation of China (82550107, 82130064, 32470177, U24A20348 and U22A20337), and the Natural Science Foundation of Wuhan (2024040701010047).
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M.H. and W.W. co-performed the experiments. M.H., W.W., and M.C. designed the study and wrote the paper. M.H. mainly contributed to plasmid design and construction, flow cytometry, Western blotting and data analysis. W.W. mainly contributed to the detection of pyroptosis-related biochemical indicators, flow cytometry, cell imaging and data analysis. Y.Q. and M.C. supervised the study. H.Z., C.L., C.Z., J.L. and Y.H. provided experimental assistance. All authors discussed the results and approved the manuscript.
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He, M., Wang, W., Zhou, H. et al. A synthetic system for RNA-responsive pyroptosis based on type III-E CRISPR nuclease-protease. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69179-5
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DOI: https://doi.org/10.1038/s41467-026-69179-5
