China News Weekly reporter / Peng Danni
Published in the 1056th issue of "China News Weekly" magazine on 2022.8.15
In late July, scientists from the French National Institute of Health and Medical Research, the National Centre for Scientific Research and the University of Montpellier published their article on nanorobots built from DNA in the journal Nature Communications.
Scientists use nanorobots to understand the molecular mechanisms of cellular mechanosensitivity to study many biological and pathological processes.
As early as the 1966 sci-fi movie "Amazing Journey", people had a new imagination about the treatment of diseases: from repairing and treating individual cells of the human body to deal with diseases.
In the movie, the surgeon is scaled down to a few millionths and rides a miniature submarine into the human body to perform vascular surgery.
This is not a fantasy.
In the microscopic world, scientists hope that nanorobots can reach places that humans cannot, such as blood.
If put into clinical use, they will cruise inside the human body, deliver drugs, perform cellular micro-surgeries on the scale of one billionth of a meter...opening up entirely new possibilities for human disease diagnosis and treatment.
In 2021, 16 years after Science magazine last published 125 scientific problems driving basic science research, the journal once again published 125 of the world's most cutting-edge scientific problems.
Among them, in the field of artificial intelligence, the question that bears the brunt is: Will injectable disease-fighting nanorobots become a reality?
The almighty "doctor" in the blood vessels
On the stage of the biotechnology field, in the past two years, due to the global new crown pandemic, the most "scenery" is undoubtedly the mRNA technology: the success of the two mRNA vaccines of Pfizer/BioNTech and Moderna, this new technology will be introduced Zitui has been pushed into the spotlight with hundreds of billions of dollars in revenue, making it the most profitable "dark horse" in the history of pharmaceuticals.
Humans have been discovering mRNA (messenger ribonucleic acid) for more than 60 years, but the technology has been slow to progress, hampered by key issues such as the rapid degradation of mRNA in the body.
In the 21st century, the delivery technology of lipid nanoparticles (LNP) as a carrier has solved the problems of easy degradation of mRNA in vivo and low delivery efficiency to a certain extent, which has enabled the rapid development of mRNA technology and its clinical application.
Zhao Yiping, a distinguished research professor at the Department of Physics at the University of Georgia, told China News Weekly that since the rise of nanotechnology in the 1990s, a very important driving force for its development has been the research and development of chips.
Later, however, the driving force in this field gradually shifted to medical applications.
In 2020, the Chinese Society of Micron and Nanotechnology wrote: Nanobiology, which combines nanotechnology and biomedicine, will be an important part of life science in the 21st century, and nanorobots will also be the most attractive achievement in nanobiology.
However, unlike the "robots" we usually think of, nanorobots are not some kind of metal armor with batteries, chips and other electronic devices.
Today, even the most sophisticated machining techniques cannot create traditional robots that swim inside the body.
Nanorobots synthesize and prepare molecules and micro-nano materials with special structures and functions through physical and chemical methods.
Tao Wei, Assistant Professor at Harvard Medical School and Distinguished Chair Professor at Brigham and Women's Hospital affiliated to Harvard University, is a scientist in biomedical engineering. His research focuses on intelligent drug delivery systems. "Nanobots" are very important. Good means of transport.
In an interview with "China News Weekly", he said that there are actually many effective drugs in clinical practice, but they cannot treat diseases well. One of the reasons is that the drugs cannot reach the lesions accurately and release the drugs in a targeted manner, resulting in serious toxic and side effects. , poor treatment effect, etc.
In fact, over the past 30 years, the scientific community has found that the research on using nanoparticles as carriers to achieve precise drug delivery has not achieved the expected results.
After the drug is coated with nanoparticles and injected into the blood, it can only passively circulate with the flow of the blood, and the delivery efficiency is not significantly different from that of direct injection of the drug, and the field is faced with a relatively frustrated situation.
With the rise of the field of nanorobots, new progress has been made in the precise delivery of drugs.
Nanorobots can flow autonomously in the human body, break through a series of biological barriers in the body, find diseased parts, and complete drug delivery, which is an important part of the era of precision medicine.
Taking thrombolytic drugs as an example, Zhao Yiping introduced that there is a tissue-type protease in the blood, which can prevent blood from coagulating.
In the elderly, due to changes in body functions, blood is prone to coagulation in a certain part, especially in the brain.
As a treatment, the doctor will quickly infuse the patient with a thrombolytic drug called TPA (cathoprotein activator). However, it will flow throughout the body, and in severe cases may cause the blood vessel wall to rupture somewhere, and the real need At the site of thrombectomy, the treatment efficiency is only 20%.
In 2018, his research group and collaborators published an article reporting a method that uses magnetism to guide nanorobots, allowing these nanoparticles to accumulate at the site of the thrombus, and then administer the drug, which can reduce the required drug dose by 100 times. The rate of thrombolysis was increased by 4 times.
For more difficult delivery sites, nanorobots have also shown positive potential in early breakthroughs.
The brain is the hardest place for nanobots to reach because they need to cross the blood-brain barrier—a very selective biological defense system that allows only some nutrients and certain molecules through, keeping pathogens out.
Gliomas are known as "brain killers" and are one of the most difficult tumors to treat in neurosurgery.
Due to the special location of this tumor, it is difficult to perform complete surgical resection, and the residual tumor cells become the source of future recurrence.
To treat the disease, drugs have to cross the blood-brain barrier.
In 2020, after 8 years of hard work, the team of Professor He Qiang of Harbin Institute of Technology designed a delivery strategy.
They packed the anticancer drug into a magnetic nanogel, which was "camouflaged" with a bacterial membrane, hidden in a type of immune cell called a "neutrophil."
Through the action of external magnetic and chemical fields, the nanorobots cross the blood-brain barrier to achieve active targeted drug delivery at the site of glioma.
The delivery efficiency of ordinary nanocarriers is about 0.7%. This new method increases the delivery efficiency of antitumor drugs to about 14%. The article was published in Science Robotics last year, which is an important research progress in the industry.
He Qiang said that the delivery efficiency is expected to break through in the future.
Now, in preliminary experiments, nanorobot scientists around the world have used the tiny machines in research to treat a variety of diseases.
Tao Wei pointed out that in the medical field, in addition to drug delivery, nanorobots can also be used for vaccine preparation, microscopic tissue imaging, disease detection, etc.
Because of its wide range of uses, He Qiang pointed out that nanorobots have subversive significance for the future paradigm of human disease diagnosis and treatment. "In theory, nanorobots can treat all diseases in the future."
About 10 years ago, when Zhao Yiping's parents were hospitalized for stroke disease at the same time, he became interested in how to use nanorobots in the field of stroke. In 2014, he and his collaborators published a report on the use of nanorobots in stroke treatment in the industry. first paper.
Generally speaking, physical and chemical methods are usually used for disease treatment, such as surgery and kidney stone crushing, which are the former, and drugs are the latter.
They designed a nanomotor that combines physical and chemical methods at the same time, and carries thrombolytic drugs on the robot. When they enter the stroke site, in addition to releasing drugs, they can also be released through the mechanical action of the robot and the thrombus. Unblock blocked blood vessels.
This kind of treatment idea is also called "micro-nano surgery".
Less noticed, in the field of condensed matter physics, scientists also use micro-nanobots as a model, called "active colloids," to study tumor formation and metastasis mechanisms, as well as flocks of birds, fish and other complex group behaviors in nature.
This theoretical research field has attracted extensive attention at home and abroad in recent years.
Drive and control of nanorobots
Einstein once predicted that the development of science in the future is nothing more than to continue to march into the macro world and the micro world.
Nanorobots are taking miniaturization to the end.
In 1959, in a famous lecture on nanotechnology, "There is a lot of space at the bottom of matter," Nobel Laureate in Physics Richard Feynman pioneered the early concept of nanorobots.
He believes that in the future it is possible for human beings to build a molecular-sized micro-machine, which can use molecules or even single atoms as building components to build substances in very small spaces.
A nanometer is one billionth of a meter, and a strand of hair about 50 microns wide is also 50,000 times wider than a 1 nanometer of matter.
The size of nanorobots is usually only tens to hundreds of nanometers. Beyond this range, it is difficult to generate enough driving force to propel their movement, and it also becomes a deadly thrombus in blood vessels because of its large size.
In "Fantastic Voyage," a team of scaled-down American doctors board a micron-scale submarine and enter the bloodstream of a wounded diplomat.
Although the blood fluctuation caused by each heartbeat of the diplomat makes the submarine on the verge of overturning at any time, and the human body's antibodies also attack the submarine as an enemy frantically, the heroic protagonists can still manipulate the submarine to save the danger in the blood, and finally eliminate the blood clot.
The best way to access different parts of the body is through the "highways" of the circulatory system - blood vessels.
But for very, very tiny nanomachines, the blood flow from the human body is enough to knock them over.
The smaller the object, the greater the impact of random collisions of air and water molecules, and its motion appears to be very chaotic.
Some scholars describe that controlling the movement of nanoparticles is like controlling a quadrotor drone to deliver a courier to a remote village during a storm.
Nanorobots are a highly interdisciplinary field, involving at least biology, materials, physics, chemistry, artificial intelligence, micro-nanoelectronics and so on.
Since the beginning of the 21st century, many different kinds of micro- and nano-materials and delicate molecules have been synthesized.
Researchers can make these micro- and nano-scale artificial molecules and particles move autonomously through chemical energy, electrical energy, magnetic energy, light energy and other means under simulated conditions.
Magnetic force has always been the most mainstream way to drive nanorobots to swim.
On July 21 this year, an article published in "Nature Machine Intelligence" stated that, inspired by the movement of protein motors in biological cells along cell microtubules, a research team from ETH Zurich and the University of Pennsylvania developed a magnetic artificial Microtubules for fast and reliable transport of magnetic micro-nanorobots in complex in vivo environments.
Escherichia coli, sperm cells, paramecia, etc., swim in harsh environments and find food by waving flagella and cilia.
Some scientists are also looking for inspiration to drive nanorobots from nature. For example, a team led by nanoscientist Oliver Schmidt of Chemnitz University of Technology in Germany has designed a hybrid robot based on sperm cells.
Sperm is one of the fastest moving cells. Guided by a magnetic field, the team used sperm-assembled nanorobots to deliver drugs to tumorigenic sites in the female reproductive tract. The paper was published in the journal Nanomaterials in 2018. ACS Nano.
After the nanorobots move stably and autonomously, there are two ideas on how to accurately "navigate" these microrobots to specific lesions.
The first is like the idea of today's driverless cars, which is accomplished through algorithm control + imaging system. The former is responsible for designing and planning the best route for nano-robots to reach the destination, while the latter is tracking and locating the traces of these micro-robots.
Another way of thinking is closer to science fiction.
He Qiang, a professor at Harbin Institute of Technology, introduced that it does not rely on external force, but uses biological methods to allow these micro-robots to find the lesion by themselves.
For example, just as bacteria can rely on specific signals to find food, with the advancement of biomedicine, nanorobots can be "guided" to go autonomously through some biochemical markers released at the lesion site.
At the end of 2004, a paper published in the Journal of the American Chemical Society reported for the first time an artificially prepared chemically driven nanomotor. Gold and platinum nanorods achieved autonomous motion by catalyzing hydrogen peroxide, which was considered to be the first in the field of nanorobots. articles.
In 2016, the Nobel Prize in Chemistry was awarded to three scientists for "the design and synthesis of molecular machines".
At that time, the Nobel Prize Review Committee pointed out that at present, molecular machines are in the stage of conceptual application, but in the future it is expected to be used for more accurate disease detection, drug delivery, ultra-high-density information storage, energy storage, new materials, sensors, etc. The field, the application prospect is limitless.
Around 2008, when He Qiang began to intervene in this direction, there were less than 10 papers published internationally. Today, He Qiang said, there are at least 50 domestic research groups specializing in nanorobots.
Zhao Yiping, one of the earliest Chinese scientists to carry out research on nano-robots and an outstanding research professor at the Department of Physics at the University of Georgia, told China News Weekly that, according to his observation, currently, about half of the articles in the direction of micro-nano robots are published by domestic scholars.
In a January article, The Wall Street Journal wrote that for decades, computer scientists and physicists have speculated that nanotechnology could completely reshape our lives at any time, unleashing a wave of inventions that "save humanity" .
"While things are not going the way they predicted, the nanotechnology revolution is quietly underway."
Starting in 2019, He Qiang said that the Ministry of Science and Technology of the People's Republic of China is listing nanorobots as a new and important research direction in nanomedicine; and in local governments, nanorobots have also been written into official plans.
Taking Heilongjiang Province, where he is located, as an example, in the "14th Five-Year Plan for Bioeconomic Development" issued in March this year, Heilongjiang Province proposed to vigorously cultivate demonstration bases of tens of billions of biomedical engineering industries, including accelerating the development of nanorobots. , high-throughput biochemical analyzers, automated immune analyzers and other high-end medical equipment.
There is still a long journey to preclinical
In theory, nanorobots could be ingested intravenously or orally to begin a journey inside the human body to safely degrade themselves after eliminating the source of the disease.
However, Zhang Ying, a researcher at the Key Laboratory of Molecular Nanostructure and Nanotechnology of the Chinese Academy of Sciences, and others wrote in a review article published at the end of last year that in order to meet the actual needs of biomedical applications, nanorobots have important applications in biosafety, driving, There are still many challenges in many aspects such as in vivo navigation.
Taking safety as an example, Zhang Ying et al. pointed out that the possible impact of nanorobots entering the body on the organism and how to eliminate it from the body after completing the task are issues worthy of attention.
Selecting materials with good biocompatibility, biodegradability, and reliability and safety is the key.
In vivo navigation, the current mainstream design is to precisely locate and track the movement of nanorobots in vivo through imaging technology.
However, He Qiang pointed out that today's most advanced in vivo imaging systems are still unable to "see" objects at the nano level, that is, unable to "look" at a single nano-robot, but only by tracking nano-robot clusters in real-time positioning and path planning. And the imaging speed can't keep up with the speed of the nanoparticles moving in the blood.
A breakthrough in this area is possible in the next 10 years or so.
In addition, nanorobots still have many unsolved difficulties.
For example, Tao Wei pointed out that the human environment is more complex than that of small animals, and various proteins in the blood may be adsorbed to the nanorobots, "masking" some of the original surface targeting or intelligent design, making them The true delivery efficiency in humans is not high enough.
Another challenge is that the immune system may recognize nanorobots as a threat to eliminate before they unload their loaded drug, and to address this, scientists are also working on materials that don't trigger an immune response in our bodies.
In Zhao Yiping's view, the current "nano-robots" have engines and fuels, but no "brains", and people cannot make them intelligent through chips and programming, so they are still very primitive robots, or they are called "nanomotors" "More appropriate.
The Chinese Society of Micro and Nanotechnology wrote in a popular science article published in 2020 that the currently developed nanorobots belong to the first generation, which is an organic combination of biological systems and mechanical systems; the second generation of nanorobots is directly assembled from atoms or molecules. The nano-devices with specific functions can perform complex nano-level tasks; the third-generation nano-robots will contain strong artificial intelligence and nano-computers, which are intelligent devices that can conduct human-machine dialogue.
With the rapid progress in the field of micro- and nano-robots, the ethical issues that may arise are still early, but they are also worthy of attention.
In 2020, an article "Environmental and health risks of nanorobots" published on the "Royal Society of Chemistry (RSC)" website pointed out that the potential harm of this cutting-edge technology has two aspects: First, the use of nanorobots to harm the body The second is the loss of propulsion or the loss of target control.
It also needs to be explored how the current regulatory framework fits into the progress of nanorobot R&D.
Just as there are concerns about artificial intelligence, nanorobots could also go out of control, from eradicating disease to destroying our bodies.
Some self-media also expressed concerns about the growth rate of nanorobots beyond control and self-replication.
Zhao Yiping pointed out to "China News Weekly" that this kind of worry is completely unnecessary now.
Because most of the preparation materials of nanorobots are some inanimate inorganic or organic materials, even robots assembled by DNA cannot self-replicate due to structural design and the lack of living environment such as enzymes.
"Many times, the more advanced the technology is, the greater its potential threat may actually be." He Qiang said that researchers cannot just talk about the advantages of nanorobots without talking about potential threats in order to compete for funding.
In his view, maybe 10 years from now, discussions around the ethics and legal norms of nanorobots will become a very important matter.
He Qiang said that the reason why nanorobots have not yet advanced to the clinical trial stage is that there is still a lot of research and development work to be completed from cell experiments and animal experiments to clinical trials, which are costly and time-consuming.
Some foreign startups have begun to incubate this field. For example, in 2017, a California-based startup, BionautLabs, was established. The company's micro-robots can be sent deep into the human brain to treat diseases that cannot be cured by other methods.
In April, the Daily Mail reported that the company plans to conduct the first human clinical trials of its tiny injectable robot within two years.
After the outbreak of the far-reaching public health event of the new crown epidemic, Tao Wei said that with the rapid approval and widespread use of mRNA vaccines, more and more people have begun to pay attention to the field of nanoparticles and drug delivery technology. And capital began to actively invest.
"Tao Wei described, "This kind of feeling is like, it turns out that this field is slowly explored on the country road, and then drove into the highway all at once.
"
In March of this year, an article published in the journal "Nature" titled "Micro-medical robots are jumping out of science fiction" wrote that it is clear that the robot is to be airborne to hard-to-reach tumor sites deep inside the human body. ,there's still a long way to go.
But the rise of in vivo animal experiments in this field and the growing involvement of clinicians suggest that microrobots may be setting sail on a long journey to the clinic.
(Intern Du Xi also contributed to this article)
"China News Weekly" Issue 30, 2022
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