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Review
. 2024 Aug 19;35(3):102313.
doi: 10.1016/j.omtn.2024.102313. eCollection 2024 Sep 10.

Advancements and challenges in mRNA and ribonucleoprotein-based therapies: From delivery systems to clinical applications

Zohre Eftekhari  1 , Horieh Zohrabi  1 , Akbar Oghalaie  1 , Tahereh Ebrahimi  2 , Fatemeh Sadat Shariati  3 , Mahdi Behdani  1 , Fatemeh Kazemi-Lomedasht  1
Affiliations
Review

Advancements and challenges in mRNA and ribonucleoprotein-based therapies: From delivery systems to clinical applications

Zohre Eftekhari et al. Mol Ther Nucleic Acids. .

Abstract

The use of mRNA and ribonucleoproteins (RNPs) as therapeutic agents is a promising strategy for treating diseases such as cancer and infectious diseases. This review provides recent advancements and challenges in mRNA- and RNP-based therapies, focusing on delivery systems such as lipid nanoparticles (LNPs), which ensure efficient delivery to target cells. Strategies such as microfluidic devices are employed to prepare LNPs loaded with mRNA and RNPs, demonstrating effective genome editing and protein expression in vitro and in vivo. These applications extend to cancer treatment and infectious disease management, with promising results in genome editing for cancer therapy using LNPs encapsulating Cas9 mRNA and single-guide RNA. In addition, tissue-specific targeting strategies offer potential for improved therapeutic outcomes and reduced off-target effects. Despite progress, challenges such as optimizing delivery efficiency and targeting remain. Future research should enhance delivery efficiency, explore tissue-specific targeting, investigate combination therapies, and advance clinical translation. In conclusion, mRNA- and RNP-based therapies offer a promising avenue for treating various diseases and have the potential to revolutionize medicine, providing new hope for patients worldwide.

Keywords: CRISPR-Cas9; LNPs; MT: Oligonucleotides: Therapies and Applications; RNP; delivery systems; genome editing; mRNA.

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Conflict of interest statement

The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
The differences between conventional mRNA and self-amplifying mRNA saRNA, derived from alphaviruses, self amplifies for efficient protein expression, promising high antibody titers against pathogens.
Figure 2
Figure 2
mRNA delivery systems Efficient mRNA delivery is challenging due to its size and charge.
Figure 3
Figure 3
Mechanism of action of mRNA-LNP vaccines This schematic diagram illustrates the process of how mRNA-LNP (messenger RNA-lipid nanoparticle) vaccines elicit an immune response. (1) mRNA packaging: mRNA encoding the pathogen’s spike protein is encapsulated in LNPs to protect it from degradation and aid its delivery into human cells. (2) Delivery and translation: LNPs transport mRNA into dendritic cells (DCs), mainly in the lymph nodes, where it is translated into the spike protein. (3) Antigen presentation: the spike protein is displayed on DCs via MHC molecules, activating CD4+ and CD8+ T cells. (4) T cell activation: CD4+ T cells recognize MHCII-bound spike proteins, secreting cytokines to stimulate immune responses, while CD8+ T cells recognize MHCI-bound proteins and release cytotoxic molecules to kill infected cells. (5) B cell activation and memory: B cells recognize the spike protein, producing antibodies via plasma cells and forming memory B cells for long-term immunity against future infections.
Figure 4
Figure 4
Polymer-mRNA delivery system for protein expression This schematic diagram illustrates the process of mRNA delivery using a cationic polymer carrier, highlighting the key steps involved in cellular uptake and protein expression. (1) Complex formation: the mRNA (depicted as a red strand) is complexed with a cationic polymer (depicted as a blue strand) to form a polymer-mRNA complex. The cationic polymer protects the mRNA and facilitates its delivery into the cell. (2) Cellular uptake: the polymer-mRNA complex is taken up by the cell through endocytosis, a process where the cell membrane engulfs the complex and brings it into the intracellular environment. (3) Endosomal encapsulation: once inside the cell, the polymer-mRNA complex is encapsulated within an endosome, a membrane-bound vesicle. (4) Endosomal escape: the mRNA is released from the endosome into the cytoplasm. (5) Translation and protein expression: the released mRNA is translated by the cellular machinery to produce the target protein, completing the process of gene expression.
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