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Review
. 2019 Apr 10;27(4):710-728.
doi: 10.1016/j.ymthe.2019.02.012. Epub 2019 Feb 19.

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

Piotr S Kowalski  1 , Arnab Rudra  2 , Lei Miao  1 , Daniel G Anderson  3
Affiliations
Review

Delivering the Messenger: Advances in Technologies for Therapeutic mRNA Delivery

Piotr S Kowalski et al. Mol Ther. .

Abstract

mRNA has broad potential as a therapeutic. Current clinical efforts are focused on vaccination, protein replacement therapies, and treatment of genetic diseases. The clinical translation of mRNA therapeutics has been made possible through advances in the design of mRNA manufacturing and intracellular delivery methods. However, broad application of mRNA is still limited by the need for improved delivery systems. In this review, we discuss the challenges for clinical translation of mRNA-based therapeutics, with an emphasis on recent advances in biomaterials and delivery strategies, and we present an overview of the applications of mRNA-based delivery for protein therapy, gene editing, and vaccination.

Keywords: CRISPR; biomaterials; clinical trial; gene editing; gene therapy; lipid nanoparticles; mRNA delivery; mRNA nanoparticles; mRNA vaccine; protein replacement.

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Figures

Figure 1
Figure 1
Schematic Representation of Extra- and Intracellular Barriers for mRNA Delivery
Figure 2
Figure 2
Representative Structures of Various Classes of Materials Developed for mRNA Delivery
Figure 3
Figure 3
Non-amplifying and Self-Amplifying mRNA Vaccine and Adaptive Immune Response (A) Schematic structure of conventional non-amplifying mRNA vaccine. (B) Schematic structure of self-amplifying mRNA vaccine (replicon), which contains the sequence-encoding antigens and the non-structural proteins that facilitate RNA capping and replication. (C) An illustration of mRNA vaccine or replicon encapsulated into nanoparticles for improved in vivo performance. (D) The process of antigen presentation and adaptive immune activation after subcutaneous injection of mRNA vaccine LNPs. Briefly, the mRNA vaccine can be captured by antigen-presenting cells (APCs; macrophages or dendritic cells) at the injection site and transported to a draining lymph node, where mRNA is translated into protein and processed by proteasome in the APCs. Then it is presented by major histocompatibility complex (MHC) class I or MHC class II molecules to CD8+ T cells or CD4+ T cells, thus activating both cellular and humoral responses.
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