Cells become "tiny doctors" in the place of humans!? —Toward a future society where we entrust our "will" to cells, aiming for an enriched quality of life—

In the society of the future, simply increasing productivity as the population declines and the labor force shrinks will not necessarily ensure that each of us can live truly happy lives. Sustainable growth and a society where diverse people can coexist require not just efficiency, but fulfillment of "quality of life (QOL)," including "living in one's own way," "environments where people feel secure," childcare, leisure time, social participation, and health and peace of mind.

To support this "quality of life," cells will work as "tiny doctors" inside our bodies...

This future, reminiscent of comics and movies, is being pursued through research by Niko Kimura, a performer for the Moonshot Goal 1 Yamanishi Project and Senior Assistant Professor at the Institute of Engineering, Tokyo University of Agriculture and Technology. Her approach to phenomena occurring in the nanometer world reflects a strong will and dream to fundamentally change the nature of future healthcare.

First, could you give us an overview of your research paper recently published in the academic journal Small (Wiley Publications) on June 9?

Kimura: This research is based on a unique live-cell function naturally possessed by "neutrophils," a type of white blood cell. Neutrophils are one of the immune cells that are the first to rush to inflammation sites in our body and have the characteristic of automatically "dying" at the site. The purpose of this research is to explore whether this natural function can be applied as a means of delivering nanometer-sized particles—including desired small artifacts such as messenger RNA (mRNA) vaccines and new gene therapy drugs—in a more "location-selective" manner.

Conventional nanomedicines composed of biocompatible nanoparticles, designed to minimize side effects, had limitations with regard to controlling their transport after intravenous administration into the body. Due to rapid diffusion, it was difficult to selectively deliver them to the true intended target location.

However, by utilizing the special abilities that cells naturally possess, we have now demonstrated the possibility of "targeted delivery" that was previously impossible.

So you're using the "selectivity" that neutrophils possess not for natural immune responses but for transporting nanoparticles introduced from outside the body. Has this kind of idea existed for a long time?

Kimura: No, the approach of using neutrophils as drug carriers is an idea from the past few years. Research is gradually beginning overseas, and it has been attracting attention for about five years now.

Loading nanoparticles (sensor particles) into neutrophils and having them transported to targets utilizes neutrophils' inherent functions. In the future, will neutrophils themselves play the role of a drug delivery system (DDS) carrying various therapeutic agents?

Kimura: Yes. However, in the future, I think the "cargo" might not necessarily need to be limited to "pharmaceuticals," and the "carrier" might not need to be limited to "neutrophils" either. If we utilize the functions that cells possess, we should be able to provide medical care that was previously impossible.

The field of cell engineering has been greatly advanced today, so we expect that various designed genes could be applied not only to neutrophils but also to other cells collected from the body or cultured cells, giving them desired functions.

Also, in terms of cell engineering, I expect that we could enhance the selectivity and functions of neutrophils themselves. Using gene editing technology and other methods, we're looking into enhancing cells' selectivity and capabilities, or giving them completely new functions. For example, if we artificially create cells that sense nanoparticles in specific environments and die in response, we should be able to create cells that can deliver particles to places where neutrophils cannot reach, such as places unrelated to inflammation.

By using cellular functions themselves in this way, even more advanced medical care could be realized. This is the concept of the "Cybernetic Avatar" (CA) in the Moonshot Goal 1 Yamanishi Project, and the future we're aiming for. In fact, the Yamanishi Project is designing various immune cells, cancer cells, senescent cells, etc. as "actors" and attempting to control interactions between cells, that is, cell-cell communications. Ultimately, we aim to realize "intracellular CA" that entrusts our "thoughts and will" to cells and moves as we intend in places that we cannot easily approach.

Does this mean we can load our will onto both "particles" and "cells"?

Kimura: That's right. For example, we can load the will "we want you to sense" onto particles, and the will "we want you to deliver particles" onto cells. Each can be said to become a CA. Furthermore, in the future, it will be possible to pack various functions such as therapeutic drugs and diagnostic functions into particles.

Is it possible to have a future where we create "tiny doctors" inside the body?

Kimura: Yes. For example, I believe there's a future in which cells that can determine "whether you're likely to get cancer" or cells that will automatically treat you after an examination will be realized. The appeal of this research is that we can envision a variety of scenarios.

Our aim is to realize communication between cells in the body according to our intentions. For that, the first step is "visualization," or observing whether exchanges are actually occurring as designed.

In this research, we visualized in real time whether neutrophils carry sensor particles and whether the intended communication occurs with macrophages and senescent cells at inflammation sites. It has also become clear that the way communication occurs differs depending on the cell type.

By the way, how large are nanoparticles?

Kimura: About the size of a virus, meaning around 100 nanometers (one nanometer is one billionth of a meter). They can't be seen with a normal optical microscope. In our research, we also use a transmission electron microscope (TEM) when viewing particle structures.

My original specialty is in technology for producing lipid-based nanoparticles with controlled physical characteristics such as size. I started with developing technology using microfluidic chips to easily produce lipid-based nanoparticles. Since then, I have been engaged in research such as visualizing and evaluating behavior when produced nanoparticles are administered to living organisms and cells and their dependence on particle properties, as well as actually putting drugs like RNA inside particles and evaluating the efficiency of gene therapy in living organisms.

Do you create the nanoparticles yourself?

Kimura: The sensor nanoparticles designed for this study contain purchased quantum sensor particles. We perform the processes of adding environmental sensing functions according to our research purposes and covering them with lipid membranes using microfluidic chips ourselves.

In particular, it's important to design the lipid composition, stiffness, membrane fluidity, etc. according to the "preferences for physical characteristics of nanoparticles" of cells.

So efficient loading onto CA cell membrane surfaces and inside cells is the theme?

Kimura: That's right. The core of the technology is particle design for effective uptake of nanoparticles by neutrophils. By designing the composition and fluidity of lipid membranes based on the cells' preferences for particle physical characteristics, we achieve increasing the uptake efficiency.

In the case of drugs, delivery is one-way, but in the future, a "mechanism" to receive information from cells will also be necessary, right?

Kimura: How to extract information and enable communication between people and cells is indeed a future challenge. Currently, we can trace sensor particles for long periods in test tubes. To apply this to humans, we'll need to think about mechanisms such as amplifying signals or detecting them from outside the body using magnetic fields or light.

Finally, please tell us about your expectations for future challenges and directions

Kimura: I wrote this paper aiming to convey not only the nano/micro technology but also the concept. Looking ahead, a major goal is to control not just communication between two types of cells, but among three or four types—even more complex coordination within the body. If we can design coordination at the cellular level, new paths should open for health maintenance and disease treatment. "From the tiny world to great health" is our dream.