April 22, 2024

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The new era of nanomedicine+mRNA is coming

The new era of nanomedicine+mRNA is coming



The new era of nanomedicine+mRNA is coming

The intersection of genetics and nanomedicine has found a place in the clinic since the early 1990s and has been one of the game-changers of the past decade, through the rapid development of much-needed therapeutic platforms , holds great promise in the fight against everything from cancer to infectious and genetic disorders.

The successful development and widespread vaccination of the mRNA COVID-19 vaccine, which has contributed greatly to stopping the COVID-19 pandemic, is a monument to decades of research progress at the intersection of genetics and nanomedicine, and has ushered in a new era of mRNA vaccine technology and manufacturing , this intersection will also go down in history as one of the greatest achievements in scientific and medical research.

The new era of nanomedicine+mRNA is coming

When Genetics Meets Nanomedicine

In the history of the development of genetics, there are so many brilliant scientists’ names.

The first was Mendel , who proposed a novel concept—the genetic factor is granular, and this genetic factor was later named gene (Gene) .

In the second half of the 20th century, French geneticist Jérôme Lejeune discovered that chromosomal abnormalities cause Down syndrome, which also pioneered medical cytogenetics.

Most importantly, James Watson , Francis Crick , and Rosalind Franklin discovered the double helix structure of DNA in 1953, paving the way for the molecular era of genetics and medicine.

In the mid-1950s, André Boivin proposed the possible involvement of RNA in heredity, noting that “the macromolecular deoxyribonucleic acid (DNA) controls the production of the macromolecular ribonucleic acid (RNA) , which together control the manufacture of enzymes in the cytoplasm.

However, There was a lack of evidence to support the theory at the time, so little attention was paid to these delicate RNA molecules.

Until 1961, mRNA (messenger RNA) was discovered. At that time, Sydney Brenner et al. found that RNA is a fragile intermediate molecule that can copy information from DNA and control protein synthesis.

They concluded that stable ribosomal RNA does not Including protein-coding information, the genetic code is translated by transient mRNA, and ribosomes make proteins according to the instructions provided by the mRNA.

In 1969, Raymond Lockard and Jerry Lingrel collaborated to present the first evidence of in vitro mRNA translation.

The new era of nanomedicine+mRNA is comingFrom the discovery of mRNA to the arrival of mRNA-nanomedicine

In 1976, Robert Langer published a paper in Nature, which first reported the use of nanoparticles and microparticles to package nucleic acids (including DNA and RNA) , which made it possible to use DNA or RNA as therapeutic drugs.

Two years later, mRNA was delivered to lymphocytes for the first time via liposomes, which further expanded the application of mRNA technology.

In 1989, a non-pegylated cationic liposome was used for mRNA delivery. In 1994, PEG was added to the surface of nanoparticles to prevent their aggregation and nonspecific uptake in macrophages and hepatocytes.

During this time, mRNA has received increasing attention as a possible therapeutic approach.

In 1990, naked mRNA was injected into mouse muscles as a potential therapeutic molecule, which laid the foundation for in vivo expression of mRNA as a therapeutic tool.

In 1992, Gustav Jirikowski used mRNA to temporarily repair urinary incontinence in rats deficient in vasopressin.

Although the concept of mRNA vaccines as nanomedicine is relatively new, it actually dates back to 1993, when Frédéric Martinon et al. first developed a nanoparticle delivery system for mRNA encoding the nucleoprotein of influenza virus. In 1995, Robert Conry et al. developed the first mRNA vaccine encoding a cancer antigen.

In 1997, Merix Bioscience, the first mRNA company, was established.

In 2005, Katalin Karikó and Drew Weissman published a paper in the journal Immunity, reporting for the first time that the modification of mRNA nucleosides can greatly reduce the immune response caused by mRNA, and can also improve the translation efficiency of mRNA, so that mRNA vaccines can be used at a higher rate Doses are injected, resulting in more antibody responses and fewer nasty side effects like fever, chills, and pain.

 

From 2008 to 2013, RNA-based gene editing tools, ZFN, TALEN and CRSIPR were successively developed. In the ensuing years, a series of mRNA vaccines targeting infectious diseases, hypersensitivity diseases, and cancer began preclinical and clinical trials.

In 2009, CureVac launched the first clinical trial of an mRNA cancer vaccine. In 2020, the mRNA COVID-19 vaccine will carry out clinical trials and obtain FDA emergency use authorization that year.

Today, mRNA vaccine technology is widely used in biomedicine and nanotechnology, from gene delivery using nanoparticles to gene therapy using various nanomedicines and nanomaterials, ushering in a new era of mRNA- nanomedicine .


mRNA – a new era of nanomedicine

Before mRNA vaccines, many attenuated vaccines, or inactivated viruses, have been developed to fight infectious diseases by triggering the body’s immune system.

But the development of these vaccines is time-consuming and expensive.

In contrast, mRNA vaccines use genetic instructions to guide human cells to make proteins to activate the immune system, which has the characteristics of “plug and play”, with shorter development time and lower development and production costs.

That being the case, why did the first mRNA vaccine not hit the market until after the COVID-19 pandemic in 2020?

In the early days of mRNA research, there was tremendous excitement about this new technology.

However, there were still some insurmountable technical obstacles to be resolved. For example, mRNA is taken up by the body and rapidly degraded before it is translated into protein in the cell, which was one of the most difficult challenges faced at the time.

In addition, the delivery of naked mRNA is also challenging because it is difficult for mRNA to efficiently cross the cell membrane.

Encapsulation of mRNA in nanoparticles facilitates protection and delivery. The emergence of lipid nanoparticles (LNP) is an important breakthrough for safe, effective and stable delivery of mRNA.

At the beginning of the COVID-19 pandemic in 2020, at this time, all the components of the mRNA vaccine are in place-the chemical modification of mRNA and the invention of LNP make the preservation and delivery of mRNA no longer difficult.

At this time, the success of the mRNA vaccine begins to enter the countdown .

The scientific community has begun to refocus its efforts on developing an mRNA COVID-19 vaccine.

Moderna and Pfizer/BioNTech have pioneered the development of two COVID-19 vaccines based on mRNA-LNP, which are more than 90% effective in preventing COVID-19.

Due to the instability of mRNA molecules, Moderna and Pfizer/BioNTech use chemical modifications to stabilize mRNAs (pseudouridine modification) and lipid nanoparticles (LNPs) to encapsulate and deliver these mRNAs.

After these mRNA-LNPs are injected into the body, the LNP will deliver the mRNA expressing the spike protein of the new coronavirus into the cells, and express the spike protein in the cells, thereby preparing the human immune system to recognize the new coronavirus.

In 2020, the FDA approved two mRNA vaccines developed by Moderna and Pfizer/BioNTech. This is the first mRNA vaccine approved for production in human history in one year.

Now, the next step may be to realize an oral or nasal inhalation multimodal nanovaccine with targeted delivery of synthetic mRNA to the respiratory tract to enhance the vaccine’s immunostimulatory activity.

Oral or nasal inhalation vaccines can reduce patient hesitation and increase compliance. Another advantage of the intranasal inhalation method is that it is convenient for co-vaccination with other vaccines.

By simply modifying the vaccine, it can adapt to new variants of the virus, combine mucosal and systemic immune responses, protect the distal mucosa, and develop powerful vaccines faster. 

In addition, mRNA technology can more easily develop multivalent vaccines to protect against multiple strains at the same time, which can be used as a unique tool to fight against possible future pandemics.

The development of mRNA vaccines for different diseases will undoubtedly become the focus of the medical and health field.

Several mRNA vaccines are currently being developed to prevent and treat a variety of diseases, including prophylactic vaccines against Epstein-Barr virus, cytomegalovirus, seasonal influenza, respiratory syncytial virus, herpes simplex virus, hepatitis B virus, HIV virus, and therapeutic vaccines against cancer.

Although these vaccines still face some challenges, such as regulatory issues, large-scale production, public accessibility, and the potential difficulty in inducing an adequate protective immune response against specific pathogens, they also offer some advantages over traditional vaccines, including Safety, efficacy, rapid preparation and adaptability.

A major future goal of the scientific community and pharmaceutical companies should be to focus on the development of novel and specific delivery systems that can withstand multiple biological barriers and reach the target site, thereby providing long-term protective or therapeutic effects.

Based on recent advances in mRNA technology and delivery vehicle technology, researchers are now able to develop mRNA vaccines for emerging infectious diseases, rare diseases, and previously neglected diseases.

mRNA – the future of nanotechnology

With the rapid development and production of mRNA technology without the need for large-scale manufacturing facilities, researchers around the world are rapidly developing new, breakthrough disease diagnostic and therapeutic applications based on mRNA technology.

Furthermore, mRNA vaccines are produced through biochemical rather than biological processes, whereas traditional vaccine technologies rely on cell culture or other means (such as production of inactivated virus vaccines in eggs) . Therefore, the production process of mRNA vaccines is simpler and more reliable.

Due to the simple production process, the time required to produce mRNA vaccines is also greatly shortened.

Compared with the one-month production cycle of viral vector vaccines and DNA vaccines, mRNA vaccines only need 3-7 days. Moreover, the entire production process does not require cell culture, so even pharmaceutical companies without previous expertise in vaccine production can quickly and mass-produce mRNA vaccines.

Today, billions of dollars have been invested in the field of mRNA therapy, and more and more biotechnology companies, including Moderna, CureVac, BioNTech, Translate Bio, eTheRNA and Cenopharma, etc. A range of mRNA therapeutics or vaccines have been developed in the areas of vascular and infectious diseases.

The new era of nanomedicine+mRNA is coming

In fact, according to the website ClinicalTrials.gov, in addition to COVID-19, more than 200 mRNA vaccines have completed clinical trials or are actively recruiting participants for clinical trials, including nearly 100 mRNA vaccines for cancer. 100 items.

Based on the results of these studies, we know that the risk-benefit profile of a vaccine must strike the right balance between immune and inflammatory activation.

In addition, results from early-stage cancer clinical trials of mRNA cancer vaccines as monotherapy or in combination with immune checkpoint inhibitors have shown positive results.

This suggests that these mRNA vaccines are effective even against complex diseases such as cancer or AIDS.

From a clinical perspective, mRNA vaccines have the potential to provide broad-spectrum immunity.

Since mRNA vaccines are limited only by the effectiveness of the recipient’s immune system against the disease, if a promising candidate protein is found, targeting the corresponding mRNA is a simple task. With a rapid production pipeline in place, mRNA vaccine technology can be developed, produced and distributed within 1-3 months of the emergence of a new pathogen.

In the future, next-generation lipid nanoparticles (LNPs) will face new challenges, such as improving their stability and multifunctionality, which should be considered in their design to increase their tolerability and safety.

Future developments also include single-dose second-generation vaccines and multivalent vaccines against multiple mutant strains that may provide protection against emerging viruses.

Personalized vaccines, another future application of mRNA vaccines, are manufactured using generic methods that can be used to rapidly produce mRNA vaccines targeting patient-specific antigens.

In addition to direct immunization of patients, mRNA can be used in cell therapy by transfecting patient-derived cells in vitro to alter cell phenotype or function, and then expanding and reinfusing these cells back into the patient.

In addition, artificial intelligence and machine learning will certainly help to design highly structured “superfolder” mRNA strands and make mRNA vaccines safer, easier to store and transport.

A multi-pronged approach to reduce the world’s significant disease burden through more widely available, affordable, effective and safe mRNA vaccines is of paramount importance.

Another potential development of mRNA-nanotechnology would be self-expanding vaccines protected and delivered by stable nanoparticles or topical scaffold patches (e.g. microneedles) that could replicate themselves in vivo after a single injection, thereby Reduced doses of injections, even booster injections are not required.

mRNA therapeutics can better link the biology of human physiological systems with novel mRNA payloads and in vivo nano-delivery systems, providing continuous drug delivery with acceptable safety and greater precision, length, and duration, which could potentially is the key to its success.

This is a new era of mRNA vaccine technology and manufacturing, a monument to decades of research progress at the intersection of genetics and nanomedicine that will go down in history as one of the greatest achievements in scientific and medical research.

Paper link :
https://www.nature.com/articles/s41565-023-01347-w

The new era of nanomedicine+mRNA is coming

(source:internet, reference only)


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