Extracellular Vesicle‐Delivered tRF‐His‐GTG‐1 Reprograms Neutrophil Lipophagy and Triggers Inflammation in COVID‐19

Immunometabolism and neutrophil extracellular traps (NETs) play pivotal roles in the pathogenesis of coronavirus disease 2019 (COVID-19) and its postacute sequelae. However, the upstream regulators that reprogram neutrophil lipid metabolism and trigger excessive NET formation remain largely undefined. This study identifies a transfer RNA-derived fragment, tRF-His-GTG-1, enriched in platelet-derived extracellular vesicles, as a key driver of neutrophil lipophagy dysfunction and inflammation in COVID-19. The use on neutrophils from 60 patients and 20 healthy controls, a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected hamster model, and multiple in vitro assays shows that severe COVID-19 and long COVID are characterized by increased lipid droplet (LD) accumulation and NET release. Mechanistically, tRF-His-GTG-1 activates Toll-like receptor 8 (TLR8)-mammalian 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-His-GTG-1 inhibitor restores lipophagy, reduces LD and NET levels, and suppresses interleukin 1beta (IL-1β)/IL-8 production in patient-derived neutrophils. These findings reveal a novel EV-mediated immunometabolic axis linking platelets to neutrophil dysfunction, and position tRF-His-GTG-1 as a promising RNA-based therapeutic target for COVID-19-associated hyperinflammation.