Data availability
All data supporting the findings of this study are available within the Article and its Supplementary Information. Source data are provided with this paper. The raw data of sequencing have been deposited at the NCBI Gene Expression Omnibus under accession number: PRJNA1328038 & PRJNA1347866. Source data are provided with this paper.
References
-
Gyawali, B., Ramakrishna, K. & Dhamoon, A. S. Sepsis: The evolution in definition, pathophysiology, and management. SAGE Open Med. 7, 2050312119835043 (2019).
-
Rudd, K. E. et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet 395, 200–211 (2020).
-
Hsu, C. G., Li, W., Sowden, M., Chavez, C. L. & Berk, B. C. Pnpt1 mediates NLRP3 inflammasome activation by MAVS and metabolic reprogramming in macrophages. Cell Mol. Immunol. 20, 131–142 (2023).
-
Fu, J. & Wu, H. Structural mechanisms of NLRP3 inflammasome assembly and activation. Annu. Rev. Immunol. 41, 301–316 (2023).
-
Swanson, K. V., Deng, M. & Ting, J. P. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 19, 477–489 (2019).
-
Liang, S. et al. GITR exacerbates lysophosphatidylcholine-induced macrophage pyroptosis in sepsis via posttranslational regulation of NLRP3. Cell Mol. Immunol. 21, 674–688 (2024).
-
Lan, J., Xu, B., Shi, X., Pan, Q. & Tao, Q. WTAP-mediated N(6)-methyladenosine modification of NLRP3 mRNA in kidney injury of diabetic nephropathy. Cell Mol. Biol. Lett. 27, 51 (2022).
-
Konermann, S. et al. Transcriptome engineering with RNA-targeting type VI-D CRISPR effectors. Cell 173, 665–676.e614 (2018).
-
Li, B. et al. Supramolecular genome editing: Targeted gelivery and endogenous activation of CRISPR/Cas9 by dynamic host-guest recognition. Angew. Chem. Int. Ed. Engl. 63, e202316323 (2024).
-
Yan, X., Pan, Q., Xin, H., Chen, Y. & Ping, Y. Genome-editing prodrug: Targeted delivery and conditional stabilization of CRISPR-Cas9 for precision therapy of inflammatory disease. Sci. Adv. 7, eabj0624 (2021).
-
Qing, S. et al. Biomineralized bacterial outer membrane vesicles potentiate safe and efficient tumor microenvironment reprogramming for anticancer therapy. Adv. Mater. 32, e2002085 (2020).
-
Kang, W. S. et al. A macrophage-specific synthetic promoter for therapeutic application of adiponectin. Gene Ther. 21, 353–362 (2014).
-
Zheng, X. et al. Combination therapy with resveratrol and celastrol using folic acid-functionalized exosomes enhances the therapeutic efficacy of sepsis. Adv. Healthc. Mater. 12, 2301325 (2023).
-
Fan, L. et al. Exosome-based mitochondrial delivery of circRNA mSCAR alleviates sepsis by orchestrating macrophage activation. Adv. Sci. 10, 2205692 (2023).
-
Chen, W. et al. Macrophage-targeted nanomedicine for the diagnosis and treatment of atherosclerosis. Nat. Rev. Cardiol. 19, 228–249 (2022).
-
Yang, Y. et al. Targeted silver nanoparticles for rheumatoid arthritis therapy via macrophage apoptosis and Re-polarization. Biomaterials 264, 120390 (2021).
-
Zhou, X. et al. Targeted therapy of rheumatoid arthritis via macrophage repolarization. Drug Deliv. 28, 2447–2459 (2021).
-
Zhang, W. et al. Intratonsillar immunotherapy: a convenient and effective alternative to subcutaneous immunotherapy for allergic rhinitis. Research 8, 0581 (2025).
-
Han, R. et al. Folic acid-modified ginger-derived extracellular vesicles for targeted treatment of rheumatoid arthritis by remodeling immune microenvironment via the PI3K-AKT pathway. J. Nanobiotechnol. 23, 41 (2025).
-
Vande Walle, L. & Lamkanfi, M. Drugging the NLRP3 inflammasome: from signalling mechanisms to therapeutic targets. Nat. Rev. Drug Discov. 23, 43–66 (2024).
-
Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015).
-
Liu, Q. et al. GSNOR negatively regulates the NLRP3 inflammasome via S-nitrosation of MAPK14. Cell Mol. Immunol. 21, 561–574 (2024).
-
Maji, B. et al. Choudhary, Multidimensional chemical control of CRISPR-Cas9. Nat. Chem. Biol. 13, 9–11 (2017).
-
Dejager, L., Pinheiro, I., Dejonckheere, E. & Libert, C. Cecal ligation and puncture: the gold standard model for polymicrobial sepsis? Trends Microbiol. 19, 198–208 (2011).
-
Ugan, R. A. et al. Cadirci, Possible contribution of the neprilysin/ACE pathway to sepsis in mice. Life Sci. 258, 118177 (2020).
-
Van der Poll, T., Shankar-Hari, M. & Wiersinga, W. J. The immunology of sepsis. Immunity 54, 2450–2464 (2021).
-
Wang, B. et al. Sepsis induces non-classic innate immune memory in granulocytes. Cell Rep. 42, 113044 (2023).
-
Cox, D. B. T. et al. RNA editing with CRISPR-Cas13. Science 358, 1019–1027 (2017).
-
Özcan, A. et al. Programmable RNA targeting with the single-protein CRISPR effector Cas7-11. Nature 597, 720–725 (2021).
-
Rodda, L. B. et al. Functional SARS-CoV-2-specific immune memory persists after mild COVID-19. Cell 184, 169–183 (2021).
-
Moiani, A. et al. Lentiviral vector integration in the human genome induces alternative splicing and generates aberrant transcripts. J. Clin. Invest. 122, 1653–1666 (2012).
-
Yin, D. et al. Targeting herpes simplex virus with CRISPR-Cas9 cures herpetic stromal keratitis in mice. Nat. Biotechnol. 39, 567–577 (2021).
-
Yin, D. et al. Dendritic-cell-targeting virus-like particles as potent mRNA vaccine carriers. Nat. Biomed. Eng. 9, 185–200 (2025).
-
Wang, H. et al. Interrogation of folic acid-functionalized nanomedicines: The regulatory roles of plasma proteins reexamined. ACS Nano 4, 14779–14789 (2020).
-
Zhao, L. et al. Exploration of CRISPR/Cas9-based gene editing as therapy for osteoarthritis. Ann. Rheum. Dis. 78, 676–682 (2019).
-
Cullis, P. R. & Felgner, P. L. The 60-year evolution of lipid nanoparticles for nucleic acid delivery. Nat. Rev. Drug Discov. 23, 709–722 (2024).
-
Kalluri, R. & LeBleu, V. S. The biology, function, and biomedical applications of exosomes. Science 367, eaau6977 (2020).
-
Lu, S. et al. Pyroptosis-responsive microspheres modulate the inflammatory microenvironment to retard osteoporosis in female mice. Nat. Commun. 16, 8127 (2025).
-
Zhang, G. et al. Artificial mucus layer formed in response to ROS for the oral treatment of inflammatory bowel disease. Sci. Adv. 10, eado8222 (2024).
-
Wick, K. D. et al. Promises and challenges of personalized medicine to guide ARDS therapy. Crit. Care 25, 404 (2021).
-
Lee, D. et al. Population analysis of the Korean native duck using whole-genome sequencing data. BMC Genomics 21, 216 (2020).
Acknowledgements
This work was supported by the National Natural Science Foundation of China (82425055 to Y.P. and 82504685 to X.Y.), the Natural Science Foundation of Zhejiang Province (LMS25H300002 to X.Y.), Key R&D Program of Zhejiang (2024SSYS0028 to Y.P.), the Postdoctoral Fellowship Program of CPSF (GZB20240672 to X.Y.), and the China Postdoctoral Science Foundation (2024M762890 and 2025T180980 to X.Y.). We thank Y. Chen, F. Zhang and B. Li for help in this project. We also thank J. Pan and D. Wu of the Research and Service Center (College of Pharmaceutical Sciences, Zhejiang University) for technical assistance with qPCR analysis and confocal microscopy imaging.
Ethics declarations
Competing interests
The Authors declare the following competing interests: A patent application related to the biomineralized lentivirus platform described in this work has been filed with the China National Intellectual Property Administration by Zhejiang University, with W.X. and Y.P. as inventors (application number CN202211558965.3). The remaining authors declare no competing interests.
Peer review
Peer review information
Nature Communications thanks Yilai Shu and Jun Wang for their contribution to the peer review of this work. A peer review file is available.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Source data
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Xi, W., Xu, Y., Bao, W. et al. In vivo chemogenetic RNA editing of macrophages by bioengineered viruses for sepsis treatment. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67655-y
-
Received:
-
Accepted:
-
Published:
-
DOI: https://doi.org/10.1038/s41467-025-67655-y
