Nature's in-depth review: Where will the new generation of mRNA therapy go?

With the great success of mRNA vaccines delivered by lipid nanoparticles (LNP) in preventing the new crown, the development of mRNA vaccines and therapies has also become an area of ​​concern

The review made a detailed inventory of the development of LNP technology for the delivery of mRNA, and discussed the broad clinical application prospects and challenges that need to be solved for this technology in addition to infectious disease vaccines

The development history of lipid molecules as a means of mRNA delivery

The development history of lipid molecules as a means of mRNA delivery

The research and development activities using liposomes to deliver mRNA can be traced back to the 1970s

In 1978, researchers demonstrated in vitro experiments that the use of liposomes can deliver mRNA into cells

Although cationic lipids are very effective in delivering mRNA, they can also trigger toxic, pro-apoptotic and pro-inflammatory responses

The emergence of ionizable lipids is an important breakthrough in the development of LNP.

▲Different lipid molecular components of lipid nanoparticles (picture source: reference [2])

▲Different lipid molecular components of lipid nanoparticles (picture source: reference [2])

In addition to cationic lipids and ionizable lipid molecules, current LNPs also carry other lipid molecules , including phospholipids, cholesterol, and polyethylene glycol (PEG) modified lipid molecules

Other lipid molecules can help improve the stability, delivery efficiency, tolerance and biodistribution of LNP and other important characteristics

Clinical application of mRNA therapy in addition to infectious disease vaccines

After the success of the liposome-delivered mRNA COVID-19 vaccine, this vaccine development method has also been used to prevent infections caused by a variety of other viruses including influenza, Zika virus, respiratory syncytial virus, and cytomegalovirus.

In addition to infectious disease vaccines, the review authors also summarized the transformational applications of liposome delivery of mRNA in other fields

In the treatment of cancer, genetic diseases, and the treatment of infectious diseases, a variety of mRNA therapies have entered the stage of clinical development

▲Representative part of clinical phase mRNA therapy (data source: reference materials [1] and public information, drawing by WuXi AppTec's content team)

▲Representative part of clinical phase mRNA therapy (data source: reference materials [1] and public information, drawing by WuXi AppTec's content team)

In the treatment of cancer, mRNA is used to develop a variety of cancer vaccines .

One of the advantages of mRNA used to develop a variety of cancer vaccines is that it can express a variety of tumor-related antigens, thereby enhancing the body's immune response to tumors

Another strategy to enhance the immune response to cancer is to change the immunosuppressive effect of the tumor microenvironment by expressing cytokines locally

The manufacturing process of CAR-T therapy that uses liposomes to deliver mRNA.

The current mRNA-based protein replacement therapy mainly focuses on hereditary metabolic diseases

The research and development direction of the new generation of mRNA and LNP technology

The review author stated that based on the experience gained from current clinical research, the formulation of LNP-mRNA still has room for further optimization
.
For example, the efficiency of mRNA translation into protein can still be further improved
.
Through the engineering of the mRNA sequence, the protein coding sequence of the mRNA and the 5'and 3'untranslated sequences (UTR) can be optimized, thereby increasing the protein expression level
.
In addition, circular RNA can be used to improve the stability of mRNA and extend its half-life in vivo
.

Through the engineering of the mRNA sequence, the protein coding sequence of the mRNA and the 5'and 3'untranslated sequences (UTR) can be optimized, thereby increasing the protein expression level
.
In addition, circular RNA can be used to improve the stability of mRNA and extend its half-life in vivo
.

In terms of LNP formulation, rational design of lipid head groups and hydrophobic tails can improve cell uptake and endosomal escape efficiency
.
The author pointed out that the use of a pH-sensitive polymer (polymer) to form hybrid nanoparticles with lipid molecules may combine the best of both to improve the efficiency of mRNA delivery
.
Currently, a variety of polymers have been used to deliver mRNA
.

The rational design of lipid head groups and hydrophobic tails can improve cell uptake and endosomal escape efficiency.
Use a pH-sensitive polymer (polymer) to form hybrid nanoparticles with lipid molecules.
It may be a combination of the two.
Strengths to improve mRNA delivery efficiency

▲Polymer molecules have been used to deliver mRNA (picture source: reference [2])

▲Polymer molecules have been used to deliver mRNA (picture source: reference [2])

A key to future mRNA therapy is to complete tissue or cell-specific delivery
.
This goal can be achieved by adjusting the structure of lipid molecules
.
For example, adjusting the alkyl length of lipid molecules can cause LNP-mRNA formulations to accumulate in the liver and spleen
.
Another way is to simulate natural molecules in the human body
.
For example, neurotransmitters are endogenous compounds in the human body that can cross the blood-brain barrier
.
Lipid molecules derived from neurotransmitters can be used to deliver mRNA into the brain
.

A key to future mRNA therapy is to complete tissue or cell-specific delivery
.
This goal can be achieved by adjusting the structure of lipid molecules
.
Another way is to simulate natural molecules in the human body
.

At present, how to detect and compare the cell distribution of different LNP formulations in the human body is still a challenging task
.
However , the technology of adding "barcode" to nanoparticles is expected to complete high-throughput screening of nanoparticle cell distribution in vivo
.

The technology of adding "barcode" to nanoparticles is expected to complete high-throughput screening of nanoparticle cell distribution in vivo
.

Finally, biodegradability and versatility should be considered when designing LNP
.
Lipid molecules that can be biodegraded allow LNP to be quickly cleared from plasma and tissues, thereby improving their safety and tolerability
.
Lipid molecules that can be biodegraded have been used in mRNA-1273 and BNT162b2 new crown vaccines
.

Biodegradability and versatility should be considered when designing LNP
.

In addition to delivering mRNA, lipid molecules may have a synergistic effect with the protein encoded by mRNA
.
For example, some lipid molecules can be used as adjuvants to enhance the effectiveness of vaccines, and paclitaxel-derived lipid molecules may integrate chemotherapy and gene therapy together for the treatment of cancer
.

Lipid molecules may have a synergistic effect with the protein encoded by mRNA

mRNA has shown great therapeutic potential in multiple clinical applications
.
The development of a new generation of lipid nanoparticles and other delivery materials is expected to further expand the application range of mRNA-based therapy in the near future, which will benefit the majority of patients
.

Reference materials:

Reference materials:

[1] Hou et al.
, (2021).
Lipid nanoparticles for mRNA delivery.
Nature Reviews Materials, https://doi.
org/10.
1038/s41578-021-00358-0

[1] Hou et al.
, (2021).
Lipid nanoparticles for mRNA delivery.
Nature Reviews Materials, https://doi.
org/10.
1038/s41578-021-00358-0

[2] Chaudhary et al.
, (2021).
mRNA vaccines for infectious diseases: principles, delivery and clinical translation, Nature Reviews Drug Discovery, https://doi.
org/10.
1038/s41573-021-00283-5

[2] Chaudhary et al.
, (2021).
mRNA vaccines for infectious diseases: principles, delivery and clinical translation, Nature Reviews Drug Discovery, https://doi.
org/10.
1038/s41573-021-00283-5