Messenger RNA (mRNA) has become a new type of therapeutic agent for the prevention and treatment of various diseases. To function in vivo, mRNA requires safe, effective and stable delivery system to protect nucleic acids from degradation and allow cellular uptake and mRNA release. Lipid nanoparticles (LNPs) has become promising vectors for a variety of therapeutic approaches in the pharmaceutical industry and successfully entered the clinic for mRNA delivery. Currently, as an important part of the COVID-19 mRNA vaccine， LNPs plays a key role in effectively protecting the mRNA and transporting it to cells. Lipid nanoparticle–mRNA vaccines have been used in clinical against COVID-19, which marks a milestone for mRNA therapeutics. Nowadays, LNPs is thought to be the golden partner of mRNA.
Source: Reference 
mRNA itself has defects such as poor stability, easy degradation by nucleases in tissues, low cell entry efficiency, and low translation efficiency. When developing mRNA vaccines, it is necessary to modify mRNA and overcome these defects through special delivery technology to obtain better therapeutic effect. Materials used for mRNA delivery include liposomes, liposome analogs, polymers, and protein derivatives. At present, the delivery technology of COVID-19 mRNA vaccines on the market is LNPs material. We will introduce LNPs for mRNA delivery from the birth and development of LNPs, the development status of LNPs and the unique advantages of LNPs.
Timeline of mRNA and liposome nanoparticles (LNPS) development
The Birth And Development of LNPs
In the 1980s, Professor Pieter Cullis of the University of British Columbia discovered in research that anti-cancer drugs can spread and stay in liposomes, and these liposomes will pass through the tumor vasculature and enter the cells after being injected into the cancerous animal and release the drug. Liposomes are hollow spherical vesicles made of phospholipid bilayers. The basic structure of the cell membrane is also a phospholipid bilayer, so liposomes have good biocompatibility.
The Cullis team initially hoped to use liposomes to deliver some toxic anti-cancer drugs to tumors safely. Later in the mid-1990s, they began to try to use liposomes to deliver larger molecules, such as nucleic acid drugs (DNA or RNA).
At that time, genetic research was in full swing. The use of nucleic acid drugs to develop disease treatment methods at the genetic level has become an emerging research direction. However, it is obviously not feasible to use traditional liposomes to deliver nucleic acids into cells, because nucleic acids are negatively charged and natural lipids are also negatively charged, which means that the two will not bind well. To solve this problem, it is necessary to add positively charged lipids to liposomes to balance the negatively charged nucleic acids. However, there are no cationic lipids in nature, and positively charged lipids are highly toxic, tearing cell membranes apart.
The Cullis team has developed a new class of lipids that are charged only under specified conditions. These lipids are positively charged in acidic (low) pH environment. At this time, these lipids can bind well to negatively charged nucleic acids, but they are neutral in the blood (physiological pH environment) and can reduce the toxic effects of cationic lipids. Moreover, LNPs can be formed spontaneously when lipids dissolved in ethanol are mixed with nucleic acids dissolved in acidic buffer using microfluids.
LNPs can be absorbed by cells through endocytosis, and lipids are ionizable at low pH, and then release the delivered drugs into the cytoplasm through endosomal escape.
Since then, after continuous optimization, LNPs has gradually been used in the delivery of a variety of nucleic acid drugs. In 2018, the FDA approved the first LNPs-delivered nucleic acid drug patisiran, which is an RNA interference therapy for the treatment of transthyretin related familial amyloid polyneuropathies (TTR-FAP), which is also the first siRNA drug approved by the FDA.
The key for mRNA vaccines or drugs to work in the body is to avoid being eliminated by the body's immune system as foreign invaders. In addition to the key modifications made by Katalin Karikó and Drew Weissman to the mRNA structure, LNPs also plays a very important role in the intracellular function of mRNA. It not only protects mRNA from degradation, but also allows nucleic acid to enter the cell.
Source: Reference 
The LNPs used in Pfizer/BioNTech and Moderna's COVID-19 mRNA vaccine is a mixture of 4 types of lipid molecules, of which 3 types help to improve the stability of the particle structure, and the fourth type is ionizable lipids. Most of these lipid molecules are positively charged, bind to negatively charged mRNA, and can lose charge in the alkaline environment of the blood, thereby greatly reducing the toxicity.
The Development Status of LNPs
As a pioneer of LNPs, Professor Pieter Cullis has many LNPs technology development companies founded by him or his laboratory members, including Acuitas Therapeutics, Arbutus Biopharma, Precision NanoSystems, AbCellera, etc. Among them, the LNPs used in the mRNA vaccines developed by Pfizer/BioNTech and CureVac are all derived from Acuitas, AbCellera cooperated with Eli Lilly to develop COVID-19 antibody therapies.
Large nodes represent related entities, and edges represent agreements or patents between two entities. Smaller nodes around the entity represent patents that are determined to be related to basic vaccine technology.
UPenn, University of Pennsylvania; UBC, University of British Columbia (Source: Reference )
As of October 9, 2021, more than 60 mRNA vaccines/drugs have entered the clinic globally. Most of these vaccines/drugs use LNPs and its variants for delivery, and LNPs can also be used for delivery of other nucleic acid drugs and CRISPR gene editors.
Current status of mRNA Vaccine/Drug Development Companies, data as of October 9, 2021
Nowadays, global mRNA research and development is gradually rising, LNPs technology development companies are also gaining momentum. As a golden partner of mRNA delivery, LNPs technology has more potential to achieve greater breakthroughs after receiving more attention and investment from research and development forces.
Unique Advantages of LNPs
Compared with viral vectors, the advantages of LNPs include basically no pre-existing immunogenicity, less interference by natural immune mechanisms, no contamination by wild or recombinant live viruses, and less risk of random integration into the genome, etc. Compared with other nanocarriers, the advantage of LNPs is that researchers have in-depth research on the use of lipid carriers to deliver drugs, and they have a lot of experience in raw material control, process development, carrier quality standards, safety evaluation, etc., and LNPs has a clear development path.
Both liposomes and lipid nanoparticles have been developed and applied for nearly 30 years. Among them, the team of Professor Cullis has made a lot of contributions, but there are also many other pioneers who have accumulated a lot of successful experience and failed lessons. Thanks to all these pioneers who laid the foundation.
Until now, the bottleneck for further breakthrough of LNPs is to optimize the relationship between its distribution in vivo and efficacy/toxicity (PK-PD/TX) for different applications. Virus vectors have tropism, and LNPs also has its stubborn habits, such as tropism to liver, spleen and reticuloendothelial system (RES) and diffusion limitation in tissue interstitium. How to design better vectors for these problems, expand the application range of drug and gene delivery, optimize the effective delivery of vectors to target cells, and reduce the ineffective delivery of non-target cells are all the directions of our future efforts.
Another name for nucleic acid drugs is gene therapy. Specific gene regulation and editing molecules, including RNAi, can be classified as gene therapy. In this field, there have been scorching heat and cold winters. The premise for the breakthrough should be the advancement of scientists in the research of disease pathogenesis and gene regulation technology.
Biopharma PEG has been focusing on the development of a full range of medical applications and technologies for nanocarrier systems, including various types of nanoparticles, liposomes, micelles, etc. We are committed to providing a variety of PEG-liposome derivatives, including mPEG, DSPE lipids with different molecular weight and functional PEG.
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 Without these lipid shells, there would be no mRNA vaccines for COVID-19 (source: c&en)
 Horejs, C. From lipids to lipid nanoparticles to mRNA vaccines. Nature Reviews Materials (2021)
 Gaviria, M., Kilic, B. A network analysis of COVID-19 mRNA vaccine patents. Nature Biotechnology (2021)
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