https://doi.org/10.1016/j.xphs.2022.11.001

The Storage and In-Use Stability of mRNA Vaccines and Therapeutics: Not A Cold Case

Messenger RNA (mRNA), which is composed of ribonucleotides that carry genetic information and direct protein synthesis, is transcribed from a strand of DNA as a template. On this basis, mRNA technology can take advantage of the body’s own translation system to express proteins with multiple functions for the treatment of various diseases. Due to the advancement of mRNA synthesis and purification, modification and sequence optimization technologies, and the emerging lipid nanomaterials and other delivery systems, mRNA therapeutic regimens are becoming clinically feasible and exhibit significant reliability in mRNA stability, translation efficiency, and controlled immunogenicity. Lipid nanoparticles (LNPs), currently the leading non-viral delivery vehicles, have made many exciting advances in clinical translation as part of the COVID-19 vaccines and therefore have the potential to accelerate the clinical translation of gene drugs. Additionally, due to their small size, biocompatibility, and biodegradability, LNPs can effectively deliver nucleic acids into cells, which is particularly important for the current mRNA regimens. Therefore, the cutting-edge LNP@mRNA regimens hold great promise for cancer vaccines, infectious disease prevention, protein replacement therapy, gene editing, and rare disease treatment. To shed more lights on LNP@mRNA, this paper mainly discusses the rational of choosing LNPs as the non-viral vectors to deliver mRNA, the general rules for mRNA optimization and LNP preparation, and the various parameters affecting the delivery efficiency of LNP@mRNA, and finally summarizes the current research status as well as the current challenges. The latest research progress of LNPs in the treatment of other diseases such as oncological, cardiovascular, and infectious diseases is also given. Finally, the future applications and perspectives for LNP@mRNA are generally introduced.

/pdf/recent-advances-in-lipid-nanoparticles-for-delivery-of-mrna-1u86o4l6.pdf

Recent Advances in Lipid Nanoparticles for Delivery of mRNA

Compared to other vaccines, the inherent properties of messenger RNA (mRNA) vaccines and their interaction with lipid nanoparticles make them considerably unstable throughout their life cycles, impacting their effectiveness and global accessibility. It is imperative to improve mRNA vaccine stability and investigate the factors influencing stability. Since mRNA structure, excipients, lipid nanoparticle (LNP) delivery systems, and manufacturing processes are the primary factors affecting mRNA vaccine stability, optimizing mRNA structure and screening excipients can effectively improve mRNA vaccine stability. Moreover, improving manufacturing processes could also prepare thermally stable mRNA vaccines with safety and efficacy. Here, we review the regulatory guidance associated with mRNA vaccine stability, summarize key factors affecting mRNA vaccine stability, and propose a possible research path to improve mRNA vaccine stability.

Research Advances on the Stability of mRNA Vaccines

Lipid nanoparticles (LNPs) are currently the most promising clinical nucleic acids drug delivery vehicles. LNPs prevent the degradation of cargo nucleic acids during blood circulation. Upon entry into the cell, specific components of the lipid nanoparticles can promote the endosomal escape of nucleic acids. These are the basic properties of lipid nanoparticles as nucleic acid carriers. As LNPs exhibit hepatic aggregation characteristics, enhancing targeting out of the liver is a crucial way to improve LNPs administrated in vivo. Meanwhile, endosomal escape of nucleic acids loaded in LNPs is often considered inadequate, and therefore, much effort is devoted to enhancing the intracellular release efficiency of nucleic acids. Here, different strategies to efficiently deliver nucleic acid delivery from LNPs are concluded and their mechanisms are investigated. In addition, based on the information on LNPs that are in clinical trials or have completed clinical trials, the issues that are necessary to be approached in the clinical translation of LNPs are discussed, which it is hoped will shed light on the development of LNP nucleic acid drugs.

Lipid Nanoparticles Optimized for Targeting and Release of Nucleic Acid.

mRNA-Lipid nanoparticles (LNPs) are at the forefront of global medical research. With the development of mRNA-LNP vaccines to combat the COVID-19 pandemic, the clinical potential of this platform was unleashed. Upon administering 16 billion doses that protected billions of people, it became clear that a fraction of them witnessed mild and in some cases even severe adverse effects. Therefore, it is paramount to define the safety along with the therapeutic efficacy of the mRNA-LNP platform for the successful translation of new genetic medicines based on this technology. While mRNA was the effector molecule of this platform, the ionizable lipid component of the LNPs played an indispensable role in its success. However, both of these components possess the ability to induce undesired immunostimulation, which is an area that needs to be addressed systematically. The immune cell agitation caused by this platform is a two-edged sword as it may prove beneficial for vaccination but detrimental to other applications. Therefore, a key challenge in advancing the mRNA-LNP drug delivery platform from bench to bedside is understanding the immunostimulatory behavior of these components. Herein, we provide a detailed overview of the structural modifications and immunogenicity of synthetic mRNA. We discuss the effect of ionizable lipid structure on LNP functionality and offer a mechanistic overview of the ability of LNPs to elicit an immune response. Finally, we shed some light on the current status of this technology in clinical trials and discuss a few challenges to be addressed to advance the field. 

The Immunostimulatory Nature of mRNA Lipid Nanoparticles.

Advanced mRNA vaccines play vital roles against SARS-CoV-2. However, most current mRNA delivery platforms need to be stored at -20 °C or -70 °C due to their poor stability, which severely restricts their availability. Herein, we develop a lyophilization technique to prepare SARS-CoV-2 mRNA-lipid nanoparticle vaccines with long-term thermostability. The physiochemical properties and bioactivities of lyophilized vaccines showed no change at 25 °C over 6 months, and the lyophilized SARS-CoV-2 mRNA vaccines could elicit potent humoral and cellular immunity whether in mice, rabbits, or rhesus macaques. Furthermore, in the human trial, administration of lyophilized Omicron mRNA vaccine as a booster shot also engendered strong immunity without severe adverse events, where the titers of neutralizing antibodies against Omicron BA.1/BA.2/BA.4 were increased by at least 253-fold after a booster shot following two doses of the commercial inactivated vaccine, CoronaVac. This lyophilization platform overcomes the instability of mRNA vaccines without affecting their bioactivity and significantly improves their accessibility, particularly in remote regions. 

https://www.nature.com/articles/s41421-022-00517-9.pdf

Lyophilized mRNA-lipid nanoparticle vaccines with long-term stability and high antigenicity against SARS-CoV-2

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Lyophilized mRNA-lipid nanoparticle vaccines with long-term stability and high antigenicity against SARS-CoV-2