Zhejiang University's blockbuster research published in Nature: Humans can also "photosynthesize" to rejuvenate senescent cells

Have you ever thought that human cells can photosynthesize like plants?

The "biological battery" thylakoids are extracted from spinach, allowing animal cells to obtain energy through photosynthesis, thus rejuvenating and reversing the aging and degeneration of cells.

This is not a fantasy, but the latest research result of the Zhejiang University team.

Recently, the team of Dr. Lin Xianfeng and Professor Fan Shunwu of Orthopedics Shaw Hospital Affiliated to Zhejiang University School of Medicine and the team of Professor Tang Ruikang of the Department of Chemistry of Zhejiang University successfully extracted "biobatteries with photosynthesis" from spinach. ——Thylakoid".

By wrapping animal cell membranes in the outer layer of nanosized thylakoids for camouflage, they achieved for the first time cross-species delivery of plant thylakoids into cells with aging lesions in animals, allowing animals to Cells can also possess the energy of plant photosynthesis.

## Lin Xianfeng (left) and Chen Pengfei (right) during experimental exchanges (Source: Zhejiang University)

On December 8, Beijing time, this original scientific research result was published in the form of an article by the top international journal "Nature".

## Paper link: https://www.nature.com/articles/s41586-022-05499-y

It is worth mentioning that the oldest member of this research team is only 34 years old and the youngest is 26 years old. They are quite young and promising.

Senior editors and reviewers of "Nature" magazine also spoke highly of the latest research results of the Zhejiang University research team, calling them:

Follow the laws of nature and innovatively break through the world's difficult problem of delivering energy to cells, opening up the possibility of metabolic engineering.

Let’s take a look at how this research turned something bad into something magical.

How to recharge animal cells

Insufficient intracellular anabolism is a key factor leading to many pathological processes in the body, and the anabolism of intracellular substances requires the consumption of sufficient cells internal energy and produce reducing equivalents.

ATP serves as the "energy currency" for cellular biological processes, and the reduced form of NADPH is a key electron donor that provides reducing power for anabolism.

But under pathological conditions, it is difficult to correct the anabolism of damaged cells and increase insufficient ATP and NADPH levels to optimal concentrations.

So, to "recharge" animal cells, the first step is to find the battery.

So Lin Xianfeng put forward an idea, "Can we design a "charging" device to controllably generate ATP and NADPH in cells? 》

The picture shows the mechanism of action of this study (Source: Zhejiang University)

At this time, Tang Ruikang’s team’s chemical biology research ideas and the concept of artificial organelles opened up a new direction for research, and they also turned their attention to the natural world.

In nature, plants and animals form a perfect complementary relationship. Plants produce oxygen and sugar by absorbing carbon dioxide, while animals do the opposite.

So they thought:

Can this macroscopic complementary relationship be extended to the cellular level, by implanting photosynthetic organelles so that the plant's energy supply system can become a "biological battery" for animal cells to supply energy?

In the end, the research team chose to use thylakoids, the energy supply organelles in chloroplasts, as the raw material of the "biological battery", and obtained thylakoids through the purification of spinach extract.

The thylakoid membrane in chloroplasts is the site of the light reaction stage in photosynthesis (Source: Zhejiang University)

According to The Paper, Fan Shunwu joked:

Everyone has seen the cartoon "Popeye", and when he eats spinach, he becomes We have a lot of strength, and spinach is also the greenest vegetable in the market, so we chose spinach.

Now that there is a battery to replenish energy, where is the interface for cell charging? How to deliver thylakoids safely and accurately into the aging and degenerated cells of animals is the second problem of this research.

Lin Xianfeng explained that the human body has a complex immune system. Various types of immune cells, mainly macrophages, will actively recognize and phagocytose foreign bodies, and then dissolve them through Enzymes degrade and digest foreign matter.

"If you want to deliver plant materials into animal cells, you need to hide everything."

Team member Chen Pengfei initially tried various delivery methods such as liposome encapsulation, but the results were not satisfactory.

Until one day, he thought about whether he could use the recipient cell's own cell membrane as a carrier?

Use the principle of homologous targeting to make cells think that the thylakoids we deliver are "ourselves", thereby avoiding immune rejection in the body and realizing cross-border cell transplantation of nanoplants Thylakoid.

After continuous exploration and exploration, the team successfully disguised nano-thylakoids with cell membranes and achieved intracellular delivery of nano-thylakoids.

Liu Xin, a member of the research team and a distinguished researcher at the Biomedical Research Center of Shaw Hospital of Zhejiang University, said:

Exogenous biological materials are produced from lysosomes Escape is an important step in achieving successful delivery. We have repeatedly verified through various endocytosis inhibition experiments that animal cells no longer clear nanothylakoids as 'foreign bodies', but become part of it.

In order to restore the function of chondrocytes, the research team adopted the emerging cell membrane nano-coating technology:

#That is, using the chondrocyte membrane of mice Nanosized thylakoids are encapsulated and injected into the damaged cartilage site.

At this time, the thylakoids are still in a "sleeping state", and the way to "wake up the thylakoids" is naturally light stimulation.

Schematic diagram of light stimulation of chondrocytes (Source: Zhejiang University)

An external beam of light passes through the mouse's skin and reaches the interior of the cartilage cells. At this time, the thylakoids begin to operate and produce ATP and NADPH.

Light stimulation significantly increases the levels of ATP and NADPH in chondrocytes, and the anabolism of senescent cells is also restored.

More importantly, the joint health of the mice was significantly improved.

According to the common evaluation method of joint health level, mice with a score of 5 can return to a state of 1.5 points through treatment (the higher the score, the more severe the arthritis). Cartilage The state of cells is also equivalent to returning from a human 60-year-old to a 20-year-old.

Research results showed that CM-NTU treatment combined with light irradiation significantly reduced cartilage destruction (assessed by safranin-O staining) at 8 and 12 weeks postoperatively (Figure 5b), International Osteoarthritis Research This result is further confirmed by the OARSI score.

Mice that received ACLT and were treated with CM-NTU and light had significantly lower scores (1.45 and 1.81 at 8 and 12 weeks after surgery, respectively) compared with the ACLT control group.

An invention patent has been submitted and is expected to be applied in many fields

According to The Paper, after more than a year of experiments and analysis, the research The team has verified that after nanothylakoid enters animal cells, it can still retain proteins and other functional monomers required for photosynthesis on the thylakoid.

That is, it maintains sufficient action time and degradation stability in the body, and ensures the production of sufficient amounts of ATP and NADPH, thereby systematically reversing the metabolic state of diseased cells.

Lin Xianfeng said:

We first look for breakthroughs in the treatment of osteoarthritis, which is currently clinically teratogenic and disabling. One of the main reasons is due to the imbalance of energy metabolism of chondrocytes and the depletion of ATP and NADPH, which leads to the destruction of articular cartilage.

Fan Shunwu said in an interview that the team had simultaneously submitted the invention patent and started product transformation.

Because the key raw materials are derived from natural plants and are very safe, the cell membrane nano-coating technology has the potential for large-scale production. I believe that in the near future, this technology is expected to be used in many fields Implement the application.

Professor Francisco Cejudo, thesis review expert, believes:

The outstanding feature of this work is that the research team successfully transformed plants into miniature Interspecies transplantation of organelles into mammalian cells.

The technology to harness the plant photosynthetic system to specifically supply ATP and NADPH in mammalian cells in a light energy-dependent manner is an exciting achievement that opens up the possibility of metabolic engineering.

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