University of Osaka researchers report that liver-cell extracellular vesicles treated with secreted phospholipase A2 suppressed lung inflammation in mice and helped in models of sepsis, colitis and liver injury.

The COVID-19 pandemic made the term “cytokine storm” familiar far beyond hospital wards. In some patients, the immune system’s response to infection spirals out of control, flooding the body with inflammatory signaling molecules called cytokines. The resulting inflammation can damage the lungs and other organs, cause abnormal blood clotting and kill.

Cytokine storms are not unique to COVID-19. They occur in many severe inflammatory conditions, including sepsis, yet effective treatments remain elusive. Researchers at the University of Osaka and collaborating institutions now report a new candidate in Science Advances: specially processed extracellular vesicles that, in mice, provided strong protection against cytokine storm.

Tiny packages from cells

Extracellular vesicles are tiny, membrane-enclosed particles released by cells. They carry RNA, proteins and lipids from the cell that made them and can influence the behavior of other cells. Because some vesicles can suppress excessive inflammation, they have attracted growing interest as potential treatments.

For years, such vesicles were dismissed by many biologists as cellular debris. Over the past two decades, however, they have come to be seen as an important means of communication between cells, carrying molecular messages that can calm or provoke inflammation, help tissues repair or, in cancer, help tumors spread.

“Mesenchymal stem cell–derived extracellular vesicles are currently attracting attention” as a possible therapy for cytokine storm, said lead author Shunya Nakayama. “However, we recently discovered that extracellular vesicles derived from liver cells are even more potent.”

The team also found that the vesicles’ activity could be boosted further by treating them with an enzyme called secreted phospholipase A2, or sPLA2. Phospholipases cut apart phospholipids, the molecules that make up cell membranes, releasing fatty acids and other lipids that can themselves act as signals.

The researchers call the treated vesicles SPLEVs, short for sPLA2-reacted extracellular vesicles.

Calming inflamed lungs

To test SPLEVs, the team injected them into mice with acute respiratory distress syndrome, or ARDS, a severe form of lung injury in which fluid builds up in the air sacs and breathing becomes difficult. ARDS was a major cause of death in severe COVID-19.

“The results were very clear,” said senior author Ai Kotani. “We found that the SPLEVs strongly suppressed lung inflammation.” Fewer immune cells were present in the lungs of treated mice, and cytokine levels were substantially lower.

The vesicles appeared to work in an unexpected way. Untreated vesicles mainly targeted macrophages, immune cells that patrol tissues. SPLEVs instead preferentially bound to the lining of the lungs, acting directly on lung epithelial cells. Those cells responded by producing large amounts of lipids that protect tissue.

Lung epithelial cells line the airways and air sacs and form the barrier between the outside world and the bloodstream. In ARDS, damage to this lining allows fluid to leak into the air sacs, which is why protecting it is a major goal of treatment.

“We coined the term ‘lipid counterstorm’ to describe this effect,” Nakayama said. The idea is that a surge of protective lipids counteracts the surge of inflammatory cytokines.

Beyond the lungs

The benefits were not limited to lung injury. According to the release, SPLEVs also had beneficial effects in mouse models of sepsis, coagulopathy (abnormal blood clotting), liver injury, colitis and pneumonia.

Sepsis, a life-threatening response to infection, is one of the most important targets. A major 2020 analysis estimated that it was associated with about 11 million deaths worldwide in 2017, roughly one in five deaths globally.

Treatments for cytokine storm now include drugs that block specific inflammatory signals, such as interleukin-6, as well as steroids such as dexamethasone, which reduced deaths among hospitalized COVID-19 patients needing oxygen in a large 2020 trial. But these drugs suppress the immune system broadly or target only one signal, and they do not work for everyone.

The researchers also found that levels of lipids called lysophosphatidylglycerols rose after treatment, suggesting that these molecules may be key mediators of the protective effect. If so, it might eventually be possible to create inexpensive, cell-free synthetic versions of SPLEVs that would not require growing cells at all.

From mice to medicine

The findings are preclinical. The release gives no quantitative results, such as survival rates or the size of reductions in inflammation, and mouse models of cytokine storm do not fully capture the human condition. Many treatments that calmed inflammation in mice have failed in human trials of sepsis and ARDS.

Producing vesicles consistently and at scale, and showing that they are safe in people, would also be significant hurdles. The prospect of a synthetic, cell-free version could ease some of those challenges.

The research was supported by the Japan Society for the Promotion of Science, the Japan Agency for Medical Research and Development and the Japan Science and Technology Agency.

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Notes

1. Nakayama, S., et al. “sPLA2-reacted extracellular vesicles (SPLEVs) as a therapeutic modality for cytokine storm syndromes.” Science Advances, 31 July 2026. DOI: 10.1126/sciadv.adr9135.
2. The University of Osaka. “Weathering a cytokine storm with extracellular vesicles.” EurekAlert!, 31 July 2026. https://www.eurekalert.org/news-releases/1137990.