Lipid Nanoparticles Cause Inflammation in Cells, but Damage Can Be Reduced: Penn Preprint

The study found that lipid nanoparticles cause inflammation by damaging cellular components called endosomes, but the degree of inflammation varies.

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A recent preprint from the University of Pennsylvania (Penn) showed that lipid nanoparticles, which transport COVID-19 mRNA in COVID-19 vaccines, cause inflammation within cells. However, this inflammation can be reduced if the proper lipid nanoparticle is used.

The researchers tested several different lipid nanoparticle formulations in animals, including ALC-0315 and SM-102, used in Pfizer’s and Moderna’s COVID-19 vaccines, respectively.

They found that all the tested lipid nanoparticles cause inflammation by damaging cellular components called endosomes. However, the degree of inflammation varies depending on the degree of damage.

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Additionally, the researchers learned that a lipid nanoparticle called 4A3-SC8 induced a lower level of inflammation by causing less damage. Inflammation could also be reduced with the drug thiodigalactoside, which prevents the cell from detecting severe damage.

Since the rollout of the COVID-19 vaccines, lipid nanoparticles have become a popular technology in nanomedicine.

“Right now, the whole nanomedicine field is focused on how to amplify LNP (lipid nanoparticle) formulation for all other diseases,” Wang Yufei, a postdoctoral researcher at UPenn and one of the study’s lead authors, told The Epoch Times.

The researchers wrote in the preprint, “Our group and others have recently shown that LNPs can induce severe inflammation and worsen markers of pre-existing inflammation by up to [greater than] 10-fold.”

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Most people who took the COVID-19 vaccines did not experience severe adverse reactions, but some papers have alluded to hyperinflammatory syndromes that occur post-vaccination.

“One question is, how can we use LNPs in a safer and more efficient way? So that is one of the main purposes that we try to optimize the LNP formulation and try to understand the mechanics of LNP interaction with the whole body,” Ms. Wang said.

Lipid Nanoparticles Punch Holes in Cell Structures

The authors also explored how lipid nanoparticles cause inflammation when introduced to cells.

They exposed mice to different types of lipid nanoparticles—either by injection or inhalation—each carrying mRNA cargo. The animals were then examined 24 hours after exposure.

Normally, when cells accept a foreign substance, it is encapsulated into sacs known as endosomes. Inside the endosomes, the substance is digested and broken down to ensure nothing harmful is introduced to the cell.

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The lipid nanoparticles escape digestion by punching holes in the endosomes.

The researchers found that the larger the hole, the greater the inflammation. Furthermore, those whose mRNA information is the most expressed and amplified also tended to have the most inflammation.

The lipid nanoparticle 4A3-SC8 punched smaller holes, triggering a milder inflammatory response. Surprisingly, it also caused a robust expression of the mRNA information it carried and was the only lipid formulation that did not align with the trends.

The authors also found that blocking galectins, proteins that detect large holes in the endosomes, reduced inflammation.

Empty Lipid Nanoparticles Cause the Most Inflammation

The study also tested whether the internal mRNA cargo or the encircling lipid nanoparticles caused the most inflammation.

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“In our paper, we prepared some LNP with no cargo—that is only the lipid,” said Ms. Wang. They also tested LNP with polystyrene polymers.

“Empty LNPs lead to the highest cytokine concentrations,” the authors wrote.

Cells exposed to empty lipid nanoparticles had approximately 20-fold higher inflammation than those exposed to particles carrying mRNA and approximately 500-fold higher inflammation than those exposed to particles carrying polystyrene polymers.

Lipid Nanoparticles Reduced Lung Inflammation

Though lipid nanoparticles cause inflammation, the preprint also showed that lipid nanoparticles may benefit health in the right combinations.

The authors tested the lipid nanoparticle 4A3-SC8 with mRNA for the anti-inflammatory chemical thiodigalactoside in mice with lung injuries that mimicked acute respiratory distress. When the mice were examined hours later, inflammation was reduced.

Prior work by Penn showed that lipid nanoparticles carrying modified RNA could exacerbate inflammatory conditions.