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

## TL;DR

This study shows how a specific RNA fragment in platelet vesicles disrupts neutrophil function and causes inflammation in severe and long-term cases of COVID-19.

## Contribution

The study identifies tRF-His-GTG-1 as a novel RNA-based driver of neutrophil dysfunction and inflammation in COVID-19.

## Key findings

- tRF-His-GTG-1 activates TLR8-mTOR signaling and suppresses RAB7A, impairing lipophagy in neutrophils.
- Ex vivo treatment with a tRF-His-GTG-1 inhibitor restores lipophagy and reduces inflammation in patient-derived neutrophils.
- Platelet-derived extracellular vesicles deliver tRF-His-GTG-1, linking platelet-neutrophil interactions to hyperinflammation in COVID-19.

## Abstract

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.

This study identifies platelet‐derived extracellular vesicles as key immunometabolic regulators in COVID‐19. The delivery of tRF‐His‐GTG‐1 to neutrophils activates TLR8mTOR signaling, disrupts lipophagy, and amplifies NET‐mediated inflammation. Importantly, targeting this axis restores neutrophil homeostasis, offering a potential therapeutic strategy for acute and long COVID.