Targeted silencing of CLYBL with platelet-mimetic siRNA nanoparticles drives itaconate–mediated macrophage reprogramming and protects against sepsis-triggered lung cell deathDownload PDF Download PDF ArticleOpen accessPublished: 30 May 2026ZuoJun Huang1 na1,Jialin Zhong1 na1,Li Zhang1 na1,Xianggui Huang2 na1,Shanshan Liang1 na1,Youfeng Zhu3,Rui Zhang4,Hongzhi He4,Chengcheng Xu1,Wang Chen1,Jing Wang1,Xiaolong Wu1,Yumin Liang1,Jian Zou1 &…Shuyao Zhang ORCID: orcid.org/0000-0003-0292-49711 Cell Death Discovery (2026) Cite this article We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.SubjectsCell biologyMolecular biologyAbstractExcessive inflammation and metabolic dysregulation fuel alveolar cell death in sepsis-induced lung injury, yet effective molecular interventions are lacking. We identify citrate lyase beta-like (CLYBL) as a previously unrecognized metabolic driver of macrophage-mediated tissue damage. In a murine cecal ligation and puncture model, CLYBL was strongly upregulated in lung tissue and peritoneal macrophages. To therapeutically target this pathway, we engineered platelet-derived extracellular vesicle–coated poly(lactic-co-glycolic acid) nanoparticles (PEVs@PLGA) encapsulating CLYBL-specific small interfering RNA. This platelet-mimetic system enabled efficient, biocompatible delivery of siRNA and robust CLYBL knockdown both in vitro and in vivo. CLYBL silencing triggered accumulation of the anti-inflammatory metabolite itaconate, limited M1 macrophage polarization, and preserved alveolar epithelial integrity, thereby reducing cell death and improving pulmonary repair. Transcriptomic analysis revealed broad immunometabolic remodeling consistent with enhanced resolution of inflammation. Biosafety evaluation confirmed negligible systemic toxicity. These findings uncover CLYBL as a critical metabolic checkpoint linking macrophage activation to alveolar cell death and highlight platelet-mimetic siRNA nanoparticles as a potent therapeutic strategy. Our work provides a mechanistic and translational framework for targeting macrophage immunometabolism to prevent fatal organ damage during sepsis.The alternative text for this image may have been generated using AI.PEVs@PLGA@si-CLYBL promote itaconate accumulation, induce immune cell functional remodeling, and facilitate lung epithelial repair, offering a novel therapeutic approach for sepsis-induced lung injury (Created with BioRender.com).FundingThis study was supported by the 2024 Guangdong Provincial Basic and Applied Basic Research Fund Natural Science Foundation Project-General project, Project ID: 2024A1515010633; 2025 Annual Guangzhou City University-Institute-Enterprise Jointly Funded Project (Basic and Applied Basic Research Project), Project ID: 2025A03J3603 and 2025A03J3366; Guangdong Quality Association For Pharmacauticals, Project No.: JNUC-2025-1201; Guangdong Yiyang Healthcare Charity Foundation, Project No.: JZ2025043.Author informationAuthor notesThese authors contributed equally: ZuoJun Huang, Jialin Zhong, Li Zhang, Xianggui Huang, Shanshan Liang.Authors and AffiliationsDepartment of Pharmacy, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, PR ChinaZuoJun Huang, Jialin Zhong, Li Zhang, Shanshan Liang, Chengcheng Xu, Wang Chen, Jing Wang, Xiaolong Wu, Yumin Liang, Jian Zou & Shuyao ZhangDepartment of Pediatrics, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, PR ChinaXianggui HuangDepartment of Intensive Care Unit, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, PR ChinaYoufeng ZhuDepartment of Emergency Medicine, Guangzhou Red Cross Hospital of Jinan University, Guangzhou, PR ChinaRui Zhang & Hongzhi HeAuthorsZuoJun HuangView author publicationsSearch author on:PubMed Google ScholarJialin ZhongView author publicationsSearch author on:PubMed Google ScholarLi ZhangView author publicationsSearch author on:PubMed Google ScholarXianggui HuangView author publicationsSearch author on:PubMed Google ScholarShanshan LiangView author publicationsSearch author on:PubMed Google ScholarYoufeng ZhuView author publicationsSearch author on:PubMed Google ScholarRui ZhangView author publicationsSearch author on:PubMed Google ScholarHongzhi HeView author publicationsSearch author on:PubMed Google ScholarChengcheng XuView author publicationsSearch author on:PubMed Google ScholarWang ChenView author publicationsSearch author on:PubMed Google ScholarJing WangView author publicationsSearch author on:PubMed Google ScholarXiaolong WuView author publicationsSearch author on:PubMed Google ScholarYumin LiangView author publicationsSearch author on:PubMed Google ScholarJian ZouView author publicationsSearch author on:PubMed Google ScholarShuyao ZhangView author publicationsSearch author on:PubMed Google ScholarCorresponding authorCorrespondence to Shuyao Zhang.Ethics declarationsCompeting interestsThe authors declare no competing interests.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationFull-length, uncropped original Western blots (download DOCX )Supplemental Materials (download DOCX )Rights and permissionsOpen Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, 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 changes were made. 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