Engineers challenge conventional wisdom, showing how larger particles could revolutionize cancer immunotherapy

Researchers at Johns Hopkins have developed a new approach to delivering medical treatment using mRNA, a genetic materials that carries instructions for making proteins in cells.  A recent study published in Proceedings of the National Academy of Sciences found that larger-than-usual particles—400 nanometers in size—work best because they are the ideal size to be preferentially picked up by circulating monocytes, a type of immune cells that survey and fight abnormal cells like cancer cells. This larger size helps the treatment reduce being captured by other cells which could reduce its effectiveness.

“For years, the field believed that smaller was better when it comes to the size of nanoparticles used to deliver therapeutics. Our study turns that on its head, as we learned that larger particles are actually ideal for targeting the immune cells that fight cancer,” said  the project principal investigator Hai-Quan Mao, professor of materials science and engineering at the Whiting School of Engineering and director of Institute for NanoBioTechnology (INBT).

Previously, nanoparticles used for drug delivery and therapeutics were typically kept below 200 nanometers to avoid their capture by phagocytic cells—specialized cells that engulf and destroy foreign cells.

To create larger particles, a team led by Yizong Hu, a previous postdoctoral fellow in the Mao Lab and the INBT, assembled smaller mRNA nanoparticles into larger clusters. They did this by changing the electrical charge of the particles’ surface, which allowed them to control how the particles bonded together and ensured they remained stable after being delivered inside the body—key to effective treatment delivery.

The researchers say this discovery could lead to new cancer treatments, such as vaccines that harness the body’s own immune cells to fight cancer. It also highlights a promising way to deliver  mRNA drugs specifically to monocytes, which could be effective not only for cancer treatment but also for other therapies that involve programming immune responses.

Previously, researchers worked primarily with much smaller nanoparticles, around 100 nanometers or 200 nanometers in size. This smaller size was so commonly used that it was considered the default in scientific literature, meaning researchers automatically aimed for 100 nm nanoparticles when designing new treatments.

“I think our work points out that there is important value out of that default size range. The larger sub-micron size range between 200 nanometers and 1,000 nanometers can be great for monocytes, which are a cell type that naturally prefer eating larger particles, a phenomenon called size-dependent phagocytosis,” Hu said.

Among a large study team assembled from Whiting School of Engineering and School of Medicine at Johns Hopkins University and Northwestern University, other co-corresponding authors also include Stephany Y. Tzeng, assistant research professor in biomedical engineering, and Jordan J. Green, professor of biomedical engineering.