Leukosomes are a promising new type of nanoparticle for use in targeted drug and gene delivery. Preloaded with leukocyte proteins, the particles cloak themselves in a shroud of host protein. Researchers from the Houston Methodist Research Institute in Texas have investigated this coating to find out how they evade the host immune system.

Reaching your target behind enemy lines is easier if you can steal a uniform. Leukosomes are biomimetic lipid vesicles (liposomes) that are preloaded with host white blood cell proteins on their surface. When inside the body, they shroud themselves in host protein to slip past the immune system: it is this unknown shroud of host protein that makes them special.

When Ennio Tasciotti and colleagues in Texas and Italy compared how coated leukosomes and bare liposomes fared in the blood, they found that the liposomes were quickly swallowed up by the host immune system, whereas the leukosomes circulated far longer. In addition, the leukosomes reached sites of inflammation in greater numbers.

The researchers studied leukosomes sized from 80 to 1000 nm that coat themselves in a specific array of plasma proteins – a corona, which helps to conceal them from the deadly host immune system. This was what they investigated to find out how it might enable the stealth function of these vesicles.

Stealth mode

Tasciotti and colleagues imaged the leukosomes in mice by intra-vital microscopy. They found that the leukosomes were able to target inflamed tissue, while also circulating for longer in the blood. Moreover, the leukosomes had the ability to resist being swallowed by roaming phagocytic macrophages. In contrast, liposomes – while they did also pick up a protein corona – were more evenly spread from their point of origin and were quickly swallowed up. This induced ability to both turn on stealth mode and target specific organs was quite unexpected. Especially after the researchers analysed the protein corona and found that leukosomes adsorb fewer proteins to their surface than plain liposomes.

The final experiment of the paper seems to posit an answer: macrophage receptors. One possibility, the researchers argue, is that the macrophage receptors in the leukosome undergo receptor site–ligand binding with proteins in the blood. This effectively blocks the sites that macrophages would normally grab on to, so the leukosome goes on unimpeded.

Biomimetic particles like these have been described as Trojan horses, and were originally designed using erythrocyte membranes. Here, researchers have begun to characterize the corona – the “cloak of many colours” – an extra layer composed of hundreds of proteins that a leukosome takes on when it enters the blood of the host. Understanding this process might well help to make more bespoke, generally targeted nanoparticles, which can sneak through the immune system to deliver their precious cargo to a specific target.

Full details reported in ACS Nano.