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Precisely targeting a drug to the right part of the body is always hard, but drug delivery is at its most challenging when the therapeutic is genetic material.

Unlike other classes of biologic drugs, DNA and RNA are not stable in circulation, so scientists have used lipid capsules called liposomes to envelop the therapeutic genes and shuttle them safely to the appropriate destination.

The human body treats engineered liposomes — and all drugs — like foreign objects. Upon injection, the immune system reacts to the circulating lipid capsules, and the white blood cells known as macrophages begin engulfing and clearing the perceived intruders.

Journal of Lipid Research

In this immunofluorescence image of a mouse bone section seven days after tail-vein injection, the liposomes (red) are distributed throughout the bone marrow cells (blue) and are associated preferentially with the vasculature (green).

For many years, this phenomenon was not a problem, according to Yue Li, a researcher at Xuzhou Medical University in Jiangsu, China.

“In recent decades, countless nanoparticles have been designed for drug delivery, and there are over 20 liposomal products available on the market,” Li said.

These medicines have been shown to be safe and effective by regulatory agencies such as the United States Food and Drug Administration.

However, in a , Li, along with co–first author Ran Yao and colleagues, showed that liposomes can have a negative impact on bone marrow macrophages.

These scientists knew that as macrophages encounter and engulf liposomes, they begin to . Researchers had put this to clever use delivering fluorescent labels into immune cells during lab experiments, but Li realized that the same phenomenon might be occurring when liposomes are administered as drugs. Indeed, previous work had shown it .

To test the theory, Li and a team of researchers at the Xuzhou Medical University injected mice with liposomes and then collected macrophages from the mouse bone marrow for study. The result is stunning: Macrophages in the bone marrow underwent pro-inflammatory activation and showed signs of stress, such as lipid accumulation in the endoplasmic reticulum. This led to a decreased ability to create red blood cells and important immune cell types like monocytes.

What does this mean? Li said he thinks the finding “provides a novel consideration criteria for clinical drug trials.” That is, patients who are immunocompromised or who have bone marrow infections might need to avoid liposome drug trials.

While this may be true, the finding must be replicated in human macrophages and tissue samples before researchers can be sure. The work also should be extended beyond liposomes to other classes of .

It’s not all bad news for liposomal drugs, either. For years, researchers have worked to engineer the surface of nanoparticles to escape immune detection. The original motivation was to increase effectiveness by keeping the drug in circulation longer. Now, those modifications may have a secondary benefit: sparing the hardworking bone marrow macrophages.

This is the graphical abstract for the paper titled "Liposomes trigger bone marrow niche macrophage 'foam' cell formation and affect hematopoiesis in mice."