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However, the upstream regulators that reprogram neutrophil lipid metabolism and trigger excessive NET formation remain largely undefined. This study identifies a transfer RNA\u2010derived fragment, tRF\u2010His\u2010GTG\u20101, enriched in platelet\u2010derived extracellular vesicles, as a key driver of neutrophil lipophagy dysfunction and inflammation in COVID\u201019. The use on neutrophils from 60 patients and 20 healthy controls, a severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102)\u2013infected hamster model, and multiple in vitro assays shows that severe COVID\u201019 and long COVID are characterized by increased lipid droplet (LD) accumulation and NET release. Mechanistically, tRF\u2010His\u2010GTG\u20101 activates Toll\u2010like receptor 8 (TLR8)\u2013mammalian target of rapamycin (mTOR) signaling and suppresses RAB7A expression, changes that impair lipophagic flux. This dual pathway impairs lipophagy and promotes NET formation and proinflammatory cytokine secretion. Importantly, ex vivo treatment with a tRF\u2010His\u2010GTG\u20101 inhibitor restores lipophagy, reduces LD and NET levels, and suppresses interleukin 1beta (IL\u20101\u03b2)\/IL\u20108 production in patient\u2010derived neutrophils. These findings reveal a novel EV\u2010mediated immunometabolic axis linking platelets to neutrophil dysfunction, and position tRF\u2010His\u2010GTG\u20101 as a promising RNA\u2010based therapeutic target for COVID\u201019\u2010associated hyperinflammation.<\/jats:p>","DOI":"10.1002\/advs.202508695","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T11:45:43Z","timestamp":1768391143000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Extracellular Vesicle\u2010Delivered tRF\u2010His\u2010GTG\u20101 Reprograms Neutrophil Lipophagy and Triggers Inflammation in COVID\u201019"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7059-4228","authenticated-orcid":false,"given":"Tsai\u2010Ling","family":"Liao","sequence":"first","affiliation":[{"name":"Department of Medical Research Taichung Veterans General Hospital  Taichung Taiwan"},{"name":"Rong Hsing 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