Journal of Vaccine Research 2024, Vol.14, No.3, 95-106 http://medscipublisher.com/index.php/jvr 98 cytoplasm through endocytosis. Some of the mRNA binds to host cell ribosomes and is successfully translated, producing antigen proteins. These proteins can be degraded into antigen peptides by proteasomes in the cytoplasm and presented to cytotoxic T lymphocytes (CTLs) via the major histocompatibility complex (MHC) class I pathway; C explains the self-adjuvant effect of mRNA. The figure shows how various pattern recognition receptors (PRRs) can recognize mRNA in vitro transcription products, triggering the activation of antigen-presenting cells (APCs) and inflammatory responses (Adapted from Xu et al., 2020) Once administered, the LNP-encapsulated mRNA is taken up by host cells through endocytosis. Inside the cells, the LNPs facilitate the release of mRNA into the cytoplasm. Here, the mRNA is translated by the host cell's ribosomes into the target antigen, typically a viral protein, which then undergoes proper folding and post-translational modifications (Kim et al., 2021). The expressed protein is processed and presented on the cell surface via major histocompatibility complex (MHC) molecules. This presentation triggers a robust immune response, including both humoral and cellular immunity. The antigen-presenting cells (APCs), such as dendritic cells, play a crucial role by migrating to the lymph nodes and activating T cells and B cells. T cells help orchestrate the immune response, while B cells differentiate into plasma cells that produce specific antibodies against the antigen (Pardi et al., 2018). 3.3 Delivery systems The delivery system is a critical component of mRNA vaccines, with lipid nanoparticles (LNPs) being the most commonly used vehicle. LNPs are designed to encapsulate the mRNA and protect it from enzymatic degradation, ensuring its stability and enhancing cellular uptake. The composition of LNPs typically includes ionizable lipids, which facilitate endosomal escape, allowing the mRNA to reach the cytoplasm where translation occurs (Hassett et al., 2019). Several advancements have been made in the optimization of LNP formulations to improve their efficacy and safety. For example, the use of biodegradable ionizable lipids has shown promise in reducing potential toxicity while maintaining high levels of protein expression and immunogenicity (Zeng et al., 2020). Additionally, the development of targeted delivery systems aims to direct the LNPs to specific cell types, enhancing the vaccine's effectiveness and reducing off-target effects (Buschmann et al., 2021). Innovative delivery systems beyond LNPs are also being explored. These include polymer-based nanoparticles, peptides, and other nanomaterial-based carriers, each with unique properties that can potentially enhance the delivery and efficacy of mRNA vaccines. The choice of delivery system can significantly influence the vaccine's performance, including its ability to induce a strong and durable immune response (Liang et al., 2021). 4 Technological Advances in mRNA Vaccines 4.1 mRNA modifications and stability One of the critical challenges in the development of mRNA vaccines has been ensuring the stability and longevity of the mRNA molecule in vivo. Early mRNA constructs were highly unstable and prone to rapid degradation by ribonucleases. To address this, researchers have developed several modifications to enhance mRNA stability and reduce immunogenicity. Incorporating modified nucleosides, such as pseudouridine and N1-methyl-pseudouridine, has been shown to significantly increase mRNA stability and translation efficiency while reducing the activation of innate immune sensors (Pardi et al., 2020). The addition of a 5' cap and a poly(A) tail to the mRNA structure also plays a crucial role in enhancing its stability and translation. The 5' cap structure protects the mRNA from exonucleases and is recognized by the cellular machinery responsible for translation initiation, thereby increasing the efficiency of protein synthesis (Gote et al., 2023). Additionally, optimizing the codon usage to match the host cell's tRNA pool can further enhance the translation efficiency of the mRNA (Kim et al., 2021). 4.2 Delivery technologies Effective delivery of mRNA into cells is a critical aspect of mRNA vaccine technology. Lipid nanoparticles (LNPs) have emerged as the most successful delivery vehicles, providing protection to the mRNA and facilitating
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