During a heart attack, oxygen can’t reach cardiac muscle cells, stopping their life-sustaining rhythmic contractions. “Very soon, things go haywire,” said Dmitry Terentyev, a cardiologist at Ohio State University. At that point, doctors must restart blood flow to the heart. 

But for muscle cells that have suspended all activity, a rapid influx of oxygen can cause its own problems. As oxygen floods the cell, a huge amount of calcium rushes out of its storage compartment, the sarcoplasmic reticulum (SR). 

In normal conditions, calcium constantly moves into and out of the SR so that the muscle fibers can contract, relax, and contract again. But in restarting cardiac cells, so much calcium gets released so quickly that the machinery responsible for pumping it back into the SR gets overwhelmed. The extra ions that stay out in the main body of the cardiac cells then start to interfere with essential cellular processes, which need carefully controlled calcium levels to function properly.  

To help recovering heart cells deal with this excess calcium, Peihang Jiang and a team of researchers at Sichuan University found inspiration in a surprising place: the immune system. In a recent study in Science Advances, they wrapped a molecule that promotes calcium restorage in a nanoparticle that homes to the SR (1). They then loaded their nanoparticles into neutrophils, which seek out cells in distress.

At first, Jiang’s team encapsulated luteolin, an antioxidant that enhances calcium transport into the SR, in a nanoparticle targeted to the SR surface. Fluorescent imaging confirmed that the nanoparticles clustered in the SR of heart muscle cells in vitro. This, however, didn’t mean that the nanoparticles could locate the heart in a living body, so Jiang’s team turned to neutrophils, the first responders of the immune system.

Neutrophils roam through the circulatory system, ready to spring into action when they detect molecules associated with cellular distress. Although these white blood cells can respond to threats in multiple ways, one of their primary strategies is to extrude their insides — including DNA, histones, and antimicrobial proteins — to create neutrophil extracellular traps (NETs). “For ages, their presence was considered as a defense mechanism against microbial invasion,” said Vladimir Torchilin, a biochemist at Northeastern University who was not involved in the current study. More recently, scientists have realized that NETs develop in response to — and cause some of the symptoms of — non-infectious conditions, like cancer and cardiovascular disease (2). 

Consequently, researchers have started thinking about the therapeutic potential of NET-based medications. For example, Torchilin views the products neutrophils release as a beacon for drugs to locate inflammation within the body. “NETs represent universal targets, virtually in any disease,” he said. In contrast, Jiang’s team turned the neutrophils themselves into a drug delivery system.

In the current study, Jiang’s team extracted neutrophils from mouse bone marrow, incubated the white blood cells with the nanoparticles, and used fluorescent imaging to confirm that neutrophils accepted the cargo.

To determine whether their loaded neutrophils could deliver the nanoparticles to the SR, the researchers induced a heart attack in a group of mice. They then restarted blood flow to the animals’ hearts and injected the animals with the engineered neutrophils. The following day, the cardiac muscle cells fluoresced strongly, confirming that the nanoparticles had infiltrated the injured heart tissue. When Jiang’s team repeated the process with luteolin-filled nanoparticles, recovering mice had normal electrocardiogram readings one day and again two weeks after treatment, suggesting that precision luteolin delivery promoted rapid and sustained recovery from a heart attack.

NETs represent universal targets, virtually in any disease.
- Vladimir Torchilin, Northeastern University

Both Torchilin and Terentyev, who was also not associated with the study, were intrigued by these results, but they had some reservations. For one, neutrophils seek out injury regardless of where it occurs. This raises questions about where else drug-loaded neutrophils might release their cargo and how many would need to enter a human body to deliver an adequate dose. “I don’t know how efficient it is,” said Torchilin.

Furthermore, heart attacks and NET formation operate on different timescales. The massive release of calcium that occurs when the heart restarts causes damage immediately, whereas Torchilin pointed out that NETs take hours to form. He thought it might make more sense to load neutrophils with something that could treat scarring or promote tissue regeneration.

Terentyev agreed and said that even though regenerating damaged heart tissue has proven to be challenging, it remains an essential goal. “We have not much choice,” said Terentyev. “We need to figure out how to preserve it.”

References

1. Jiang, P. et al . Intercellular NETwork-facilitated sarcoplasmic reticulum targeting for myocardial ischemia-reperfusion injury treatment. Sci Adv  11, eadr4333 (2025).
2. Masucci, M.T. et al.  The emerging role of neutrophil extracellular traps (NETs) in tumor progression and metastasis. Front Immunol  11, 1749 (2020).