Recent Advances in the Lipid Nanoparticle-Mediated Delivery of mRNA Vaccines

Abstract

Lipid nanoparticles (LNPs) have recently emerged as one of the most advanced technologies for the highly efficient in vivo delivery of exogenous mRNA, particularly for COVID-19 vaccine delivery. LNPs comprise four different lipids: ionizable lipids, helper or neutral lipids, cholesterol, and lipids attached to polyethylene glycol (PEG). In this review, we present recent the advances and insights for the design of LNPs, as well as their composition and properties, with a subsequent discussion on the development of COVID-19 vaccines. In particular, as ionizable lipids are the most critical drivers for complexing the mRNA and in vivo delivery, the role of ionizable lipids in mRNA vaccines is discussed in detail. Furthermore, the use of LNPs as effective delivery vehicles for vaccination, genome editing, and protein replacement therapy is explained. Finally, expert opinion on LNPs for mRNA vaccines is discussed, which may address future challenges in developing mRNA vaccines using highly efficient LNPs based on a novel set of ionizable lipids. Developing highly efficient mRNA delivery systems for vaccines with improved safety against some severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants remains difficult.

Keywords: COVID-19; lipid nanoparticles; mRNA; vaccine.

Figure 1

Composition of LNPs and importance of each component.

Figure 2

Shows the different types of ionizable lipids used in the composition of LNPs.

Figure 3

Shows the addition of a SORT lipid molecule to typical four-component LNPs alters the in vivo delivery profile of the resultant five-component SORT LNPs, allowing for tissue-specific distribution of mRNA to the liver, lungs, and spleen of mice following IV injections.

Figure 4

(A). Structure and in vitro synthesis of mRNA. The basic structure of mRNA for therapeutics development. Cap, 5′ UTR, ORF, 3′ UTR, and PolyA are the five structural components of mRNA. (B). In vitro Synthesis of Modified mRNA. Mostly, vector DNA is used to construct the mRNA sequence. RNA polymerase uses the linearized DNA template containing either T7 or T3 or another promoter sequence for in vitro transcription (IVT) of mRNA. In some instances, caping and poly A addition can be done after the IVT process. However, some advanced kits are engineered to do the capping and poly A during the IVT process as a single step. More details are reviewed elsewhere [1].

Figure 5

Immune response by mRNA vaccines. LNPs are prepared by encapsulating mRNA, which encodes the viral protein of interest. Upon injection of vaccines, muscular cells take up the LNPs following the release of mRNA into the cytosol and translation of target protein with the help of host machinery. In parallel, the danger associated signals produced by the LNPs recruit the innate immune cells, including neutrophils, monocytes, macrophages, dendritic cells, and others. The antigen-presenting cells (APC) process and present the antigen to the T cells, which further polarizes into effector T cells and helps in B cell-mediated responses. The cytotoxic T cells produced upon activation kill the infected cells, and antibodies (produced by B cells or plasma cells) neutralize the virus.

Figure 6

mRNA vaccine development. The figure illustrates the sequential steps involved in the mRNA vaccine development, from design to preclinical studies. Prior to going on to the next step, quality evaluation is required at each step.