Messenger RNA (mRNA) vaccines are a novel type of vaccines that use mRNA molecules to deliver genetic information to the cells, inducing the expression of specific antigens and eliciting immune responses. mRNA vaccines have several advantages over conventional vaccines, such as high specificity, safety, scalability, and versatility. However, mRNA vaccines also face several challenges and limitations, such as instability, low transfection efficiency, and potential immunogenicity. Therefore, developing effective carrier technologies for mRNA vaccines is of great importance and significance, especially in the context of the COVID-19 pandemic and beyond. Carrier technologies are the methods and materials that can encapsulate, protect, and deliver mRNA molecules to the target cells, enhancing the stability, efficiency, and specificity of mRNA vaccines. There are various types and characteristics of carrier technologies for mRNA vaccines, such as lipid-based, polymer-based, protein-based, and hybrid carriers. Each type of carrier has its own advantages and disadvantages and can be further modified and optimized to improve performance and overcome the limitations of mRNA vaccines.
mRNA is an unstable molecule that is easily degraded by enzymes, pH changes, temperature changes, oxidative stress, and other factors. Therefore, enhancing the stability of mRNA is one of the key steps to developing effective mRNA vaccines. Carrier technologies can protect mRNA from external damage, prolong the half-life of mRNA, increase the bioavailability of mRNA, and thus improve the efficacy and safety of mRNA vaccines. Carrier technologies can enhance the stability of mRNA in different ways, such as by using chemically modified mRNA, selecting suitable carrier materials, optimizing the structure and composition of carriers, and increasing the protective and sustained release properties of carriers. Chemically modified mRNA can reduce the susceptibility of mRNA to enzymatic degradation, increase the stability of mRNA in physiological conditions, and decrease the immunogenicity of mRNA. For example, using N1-methyl pseudouridine modified mRNA can improve the stability and translation efficiency of mRNA, as well as reduce the innate immune response of mRNA. Carrier materials can also affect the stability of mRNA, depending on their physicochemical properties, such as hydrophilicity, hydrophobicity, charge, and biodegradability. For example, lipids can form bilayer structures that can encapsulate and protect mRNA from degradation, while polymers can form cross-linked networks that can entrap and sustain the release of mRNA. Carrier structure and composition can also influence the stability of mRNA, depending on their size, shape, surface properties, and components. For example, smaller and spherical carriers can have higher stability and longer circulation times than larger and irregular carriers, while PEGylated and neutral carriers can have lower opsonization and clearance than non-PEGylated and charged carriers. Carrier protection and release can also determine the stability of mRNA, depending on their interaction with the biological environment, such as blood, tissues, cells, and organelles. For example, carriers that can avoid the recognition and elimination by the immune system, escape the endocytosis and lysosomal degradation, and release the mRNA into the cytoplasm or nucleus can enhance the stability and expression of mRNA.
mRNA transfection efficiency is the ability of mRNA to successfully enter the target cells and express the encoded proteins, which is one of the important factors that determine the effect of mRNA vaccines. However, mRNA transfection efficiency in vivo is usually low because it needs to overcome the barriers of the cell membrane, endocytosis, lysosomal degradation, and nuclear entry. Carrier technologies can improve the transfection efficiency of mRNA through various methods, including the use of cationic carriers, adjusting the hydrophilicity and hydrophobicity of carriers, regulating the size and charge of carriers, and increasing the escape and release properties of carriers. Cationic carriers can facilitate the electrostatic interaction and fusion with the negatively charged cell membrane, enhancing the cellular uptake and membrane permeability of mRNA. For example, PEI or PAMAM modified LNPs can increase the transfection efficiency of mRNA by forming complexes with mRNA and inducing endosomal escape. Hydrophilicity and hydrophobicity of carriers can affect the stability and biodistribution of mRNA, influencing the delivery and expression of mRNA. For example, PVP or PVA coated LNPs can improve the transfection efficiency of mRNA by increasing the hydrophilicity and dispersity of LNPs, reducing the aggregation and clearance of LNPs. The size and charge of carriers can determine the diffusion and interaction of mRNA, affecting the penetration and targeting of mRNA. For example, smaller and neutral carriers can have higher transfection efficiency than larger and charged carriers because they can avoid the opsonization and elimination by the immune system and reach the target tissues and cells more easily. Escape and release of carriers can also determine the transfection efficiency of mRNA, depending on their ability to overcome the endosomal and nuclear barriers and deliver the mRNA to the site of action. For example, carriers that can respond to the pH or enzymatic changes in the endosomes or use nuclear localization signals can enhance the transfection efficiency of mRNA by releasing the mRNA into the cytoplasm or nucleus.
mRNA targeting specificity is the ability of mRNA to selectively reach and enter the desired cells and tissues, which is one of the important factors that determine the effect and safety of mRNA vaccines. However, mRNA targeting specificity in vivo is usually low because it needs to overcome the dilution in the blood, the obstruction of the blood vessels, the clearance of the liver, and the nonspecific cellular uptake. Carrier technologies can improve the targeting specificity of mRNA in different ways, such as using targeting ligands or antibodies modified carriers, selecting specific carrier materials, adjusting the hydrophilicity and hydrophobicity of carriers, and increasing the penetration and selectivity of carriers. Targeting ligands or antibodies can bind to the receptors or antigens on the surface of the target cells or tissues, enhancing the recognition and interaction of mRNA with the target cells or tissues. For example, using receptor-mediated targeting strategies, such as transferrin, folate, or mannose modified carriers, can improve the targeting specificity of mRNA to tumor cells, dendritic cells, or macrophages. pH-sensitive targeting strategies, such as using imidazole or histidine modified carriers, can improve the targeting specificity of mRNA to the acidic tumor microenvironment. Light-sensitive targeting strategies, such as using gold or silver nanoparticles modified carriers, can improve the targeting specificity of mRNA by applying local laser irradiation to the target site. Magnetic targeting strategies, such as using iron oxide nanoparticles as modified carriers, can improve the targeting specificity of mRNA by applying a magnetic field to the target site. Carrier materials can also affect the targeting specificity of mRNA, depending on their origin and affinity to the target cells or tissues. For example, using natural or synthetic materials that have inherent or acquired specificity to the target cells or tissues, such as albumin, protamine, or chitosan. Hydrophilicity and hydrophobicity of carriers can influence the biodistribution and accumulation of mRNA, affecting the delivery and expression of mRNA. For example, using more hydrophilic and less hydrophobic carriers can reduce the nonspecific uptake and clearance of mRNA by the liver and spleen and increase the circulation time and distribution of mRNA to the target cells or tissues. Penetration and selectivity of carriers can determine the targeting specificity of mRNA, depending on their ability to overcome extracellular and intracellular barriers and deliver the mRNA to the site of action. For example, using carriers that can penetrate the blood-brain barrier, the tumor stroma, or the cell membrane, or using carriers that can selectively release the mRNA in response to stimuli such as pH, temperature, or enzymes.
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