In 2018, Mulder and Van der Meel were working thousands of miles apart – one in New York, the other in Vancouver. Mulder, then affiliated to Mount Sinai Hospital, wanted to use his prestigious Vici grant to start a promising project at TU/e. Van der Meel, a talented researcher in nanotechnology involving RNA, turned out to be the perfect companion. A Skype call in 2018 brought them together.

Trojan horse

What made Mulder and Van der Meel the perfect match was their complementary expertise. Mulder has been working with the body’s own nanoparticles – lipoproteins – as drug transporters for years. Van der Meel specializes in RNA therapies, a promising technique for controlling the immune system. In Canada, he conducted research under the guidance of Pieter Cullis, a pioneer in nanomedicine and one of the founders of the technology behind mRNA vaccines, such as those against COVID-19. The combination of this knowledge proved revolutionary.

Nanomedicines use extremely small particles – nanoparticles – for targeted drug delivery. By delivering drugs directly to the cellular level, treatments can become more efficient and there’s less risk of side effects. A major challenge in this field, however, is developing a reliable transport system that delivers the drugs to exactly the right place in the body.

Mulder explains: “A lot of nanomedicine focuses on synthetic materials, but we actually want to utilize the body’s own structures.” The lipoproteins that Mulder and Van der Meel use naturally function as an essential transport system in the body, transporting cholesterol and other fats through the blood, among other things. “That makes them an ideal delivery system for nanomedicines,” says Mulder. “The immune system already recognizes and accepts these fat globules, so why not use them in a smart way?”

If RNA medication is wrapped in these lipoproteins, it remains more stable and can be targeted for delivery to immune cells, reducing side effects and increasing efficacy. Mulder: “We’re mimicking a natural transport system in our body. It’s like a Trojan horse: the body sees a harmless fat particle, when in reality it’s transporting a powerful drug.” Van der Meel adds: “We use biology to our advantage. Instead of outsmarting the body, we cooperate with it.”

Breakthrough in immunotherapy

“Many diseases are related to immune system problems,” Mulder explains. An overactive immune system can attack one’s own body, as happens in autoimmune diseases such as type 1 diabetes, MS, and Crohn’s disease. In other cases, the immune system responds too weakly or incorrectly, such as in cancer or chronic infections. The nanotransport system for RNA drugs that Mulder and Van der Meel are developing offers a way to target immune cells.

“With RNA, you can reprogram the immune system,” Mulder continues. “By sending exactly the right signals to immune cells, you can activate or inhibit them.” The results of laboratory experiments on mice with cancer were astounding. “We saw that tumors disappeared like snow before the sun after just one dose of our nanomedicine,” says Van der Meel. “That’s insane. We want to test this further in monkeys, because their immune system is much more like ours,” Mulder says. “The ultimate goal, of course, is to turn this into clinical applications.”

Lasting impact

From the beginning, the researchers chose a strategy focused on the long term. “Many researchers feel the pressure to get their publications out there as quickly as possible, but we wanted to build something that would really have a lasting impact,” Mulder says. To achieve great results, you must first invest in building an infrastructure that makes these possible, he emphasizes. Only then can you develop, test, and optimize technology to create something that’s both relevant and useful.

Using the Vici grant as a cornerstone, they created an environment where time and resources were freed up for in-depth research, instead of for quick publications without any lasting impact. Today, the research team consists of more than thirty people, divided between Eindhoven and Nijmegen, and is active within both TU/e and Radboud university medical center.

According to Mulder, those mutual bonds aren’t a fringe benefit, but a prerequisite to success. “For the type of research we do – where you build a big story together – a good atmosphere is essential.” The social aspect is also crucial when hiring new team members. “We can teach someone practical and technical skills, but we can’t change their attitude and how they fit into the group. Those things are even more important,” says Van der Meel.

From lab to patient

Their patience, close collaboration, and determination were rewarded. Publishing in two renowned journals – Nature Biomedical Engineering and Nature Nanotechnology – is a milestone, but for the researchers it certainly doesn’t feel like the end of the road – more like the start of the next challenge. “Such a publication would be the natural end point for many projects, but for us it’s really only the beginning,” says Van der Meel.

To bring the technology to patients, Mulder founded Biotrip, a company dedicated to developing patents and applying the technology in medical practice. Nine patent applications are already pending.

“We’re looking at different applications, from cancer to cardiovascular disease,” Mulder says. “RNA-based therapies will always need a delivery system. If we can control exactly which cells and tissues the drugs go to, that opens up a world of possibilities,” adds Van der Meel.

Their ultimate dream? “To make real impact for patients here, in Nijmegen and Eindhoven and everything in between, with our own people,” Mulder concludes. And with the speed at which their research is developing, that dream seems to be getting closer and closer.