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Nanoparticles stimulate mouse immune system to attack cancer

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Exosomes are tiny, fluid-filled sacs that are naturally released from cells into the blood and other bodily fluids. These nanoparticles facilitate communication between cells by carrying genetic information and proteins, and have long been considered a promising tool for delivering targeted drugs to specific organs. Now, in a scientific first, cancer researchers have developed multifunctional exosomes for cancer treatment and tested them in mice.

On their surface, exosomes display four different types of proteins involved in triggering an antitumor immune response in humans. The modified exosomes, called GEMINI-Exos, are described in an article published in the September 7 issue of Molecular therapy and open up the possibility of reprogramming native nanocarriers, which are safer and less likely to cause long-term adverse effects than synthetic nanoparticles, in different ways for personalized immunotherapy.

Sonia Melo, a biochemist at the Institute for Health Research and Innovation in Portugal, explains that the novelty of this research lies in the combination of different molecules on the surface of the exosome, each acting on a different mechanism within antitumor immune response. This offers the possibility of “attacking simultaneously on more than one front to defeat the enemy”: cancer.

To design the therapeutic exosomes, Yong Zhang, a biochemist at the University of Southern California (USC), and his colleagues began by identifying exosomes from human cell cultures by looking for a naturally occurring marker on their surface, known as of CD-9. They isolated the exosomes and then fused the marker on each exosome with four molecules, called PD-1, OX40L, CD3 and EGFR, which regulate immune response and cancer progression.

To test whether these modified exosomes help the immune system, Zhang and his team developed humanized mice by introducing human immune cells into immunocompromised animals. These animals were also injected subcutaneously with human breast cancer cells that turned into tumors. The mice were then injected every other day (six times in total) with the modified exosomes, while the control group received native exosomes.

When the researchers mapped tumor growth in mice treated with GEMINI-Exos for 50 days after tumor inoculation, they found that the treated mice had smaller tumors compared to the control group and a stronger antitumor immune response. stronger than mice with native exosomes. “This demonstrated to us that modified exosomes can lead to [a] a long-lasting immune response not only for breast cancer, but for many other types of cancers that can be treated with immunotherapy,” says Zhang.

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While Melo says she thinks this work could potentially lead to breakthroughs in cancer immunotherapy, there are safety issues with engineered exosomes that need to be considered. These particles contain RNA, she says, and scientists have little control over how engineering will alter the genetic information inside the exosomes. “I don’t know if I would inject myself with these artificial exosomes if I had cancer, because I know how poorly controlled the system is,” Melo says. “That’s a major downside not just to this work, but to the field itself.”

Zhang agrees that this is a barrier and stresses the need for further research to assess the therapeutic benefits, as well as the risks posed by fusing other proteins to the CD-9 marker. For now, his group is putting these questions on hold, instead testing the effectiveness of modified exosomes in other types of cancers.