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The human body naturally contains small fat particles. A well-known example is HDL, also known as good cholesterol. These particles are made from substances that the body already produces, which makes them well tolerated.

In her research, Hokke used these fat particles as the basis for a new type of drug carrier. A protein called apolipoprotein A1, or apoA1, provided the structural backbone of the particles. This protein could be fused with other proteins, giving the particles additional functions. In this way, the particles could essentially be programmed: directed toward specific cells, or equipped with substances that influence the immune system.

Keeping signaling proteins in the body longer

The immune system communicates through signaling proteins called cytokines. These proteins allow immune cells to coordinate with one another. If cytokines are used as therapy, such proteins are normally injected directly into the body. But this approach has a drawback: the kidneys filter them out of the blood quickly. As a result, high doses are needed to achieve an effect, which leads to side effects.

Hokke addressed this by fusing the cytokines with apoA1, making them part of the fat particles. The particles remained in the bloodstream longer than free-floating cytokines. They also reached the organs where immune cells are located more effectively. This could make it possible to achieve results with lower doses in the future.

Delivering to the right immune cells

Not all immune cells are the same. Depending on the disease, you want to reach different cell types. Hokke therefore developed a way to direct the fat particles toward a specific cell type: T cells, an important type of immune cell.

To do this, she used so-called nanobodies: very small proteins that fit like a key into a specific name tag on the surface of T cells. By attaching these nanobodies to the fat particles, the particles reached the correct T cells far more often. They were less likely to end up in other types of immune cells.

Hokke then investigated whether these targeted particles could also be used to deliver genetic instructions. Those instructions, in the form of mRNA, cause a cell to start producing specific proteins and take on new functions. This is similar to the technology behind the COVID-19 vaccines. By improving the composition of the particles, she succeeded in delivering mRNA efficiently to immune cells in the laboratory.

Artificial intelligence designs better recognition molecules

In the final part of her research, Hokke used artificial intelligence (AI) to design new nanobodies. This time, the targets were cells that suppress the immune system, known as regulatory cells.

She trained an AI model using results from nanobodies that had previously been tested in the laboratory. The model learned from that data and then designed new nanobodies. These newly designed proteins bound more strongly to their target than the nanobodies used to train the model. The model had therefore successfully created better recognition molecules than the laboratory experiments had produced.

From lab to treatment

The research by Hokke showed that fat particles based on apoA1 are promising drug carriers. By combining the protein with cytokines, nanobodies, or genetic instructions, the particles were able to reach the immune system more precisely in multiple ways.

The combination of biotechnology, nanotechnology, and artificial intelligence offers a promising path toward new treatments for diseases in which the immune system plays a central role, such as cancer and autoimmune conditions.

This research was conducted within ICMS (Institute for Complex Molecular Systems) at Eindhoven University of Technology, in the Precision Medicine research group led by Willem Mulder. The research was funded by an ERC Advanced Grant (TOLERANCE) from the European Research Council (ERC).