Nanomedicine-Based Approaches for mRNA Delivery

Uchida, Satoshi; Perche, Federico; Pichon, Chantal; Cabral, Horacio

doi:10.1021/acs.molpharmaceut.0c00618

Cited by 139RNA Interference and Gene DeliveryNanoparticle-Based Drug DeliveryExtracellular vesicles in disease

Nanomedicine-Based Approaches for mRNA Delivery

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Uchida, Satoshi, Perche, Federico, Pichon, Chantal, Cabral, Horacio·2020·Molecular Pharmaceutics

DOI 10.1021/acs.molpharmaceut.0c00618

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Abstract

Messenger RNA (mRNA) has immense potential for developing a wide range of therapies, including immunotherapy and protein replacement. As mRNA presents no risk of integration into the host genome and does not require nuclear entry for transfection, which allows protein production even in nondividing cells, mRNA-based approaches can be envisioned as safe and practical therapeutic strategies. Nevertheless, mRNA presents unfavorable characteristics, such as large size, immunogenicity, limited cellular uptake, and sensitivity to enzymatic degradation, which hinder its use as a therapeutic agent. While mRNA stability and immunogenicity have been ameliorated by direct modifications on the mRNA structure, further improvements in mRNA delivery are still needed for promoting its activity in biological settings. In this regard, nanomedicine has shown the ability for spatiotemporally controlling the function of a myriad of bioactive agents in vivo. Direct engineering of nanomedicine structures for loading, protecting, and releasing mRNA and navigating in biological environments can then be applied for promoting mRNA translation toward the development of effective treatments. Here, we review recent approaches aimed at enhancing mRNA function and its delivery through nanomedicines, with particular emphasis on their applications and eventual clinical translation.

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mRNA has therapeutic potential in viral vaccines, protein replacement therapies, cancer immunotherapies, cellular reprogramming and genome editing.
“mRNA has shown therapeutic potential in a range of applications, including viral vaccines, protein replacement therapies, cancer immunotherapies, cellular reprogramming and genome editing2,4,7–17.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
mRNA normally contains five structural elements: a 5′ cap, a 3′ poly(A) tail, a protein-coding sequence and 5′ and 3′ untranslated regions.
“mRNA normally contains five structural elements, that is, a 5′ cap, a 3′ poly(A) tail, a protein-coding sequence and 5′ and 3′ untranslated regions (UTRs)2,4,7,13.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
These elements can be engineered to improve the stability and translational efficiency of mRNA.
“These elements can be engineered to improve the stability and translational efficiency of mRNA2,4,7,13.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
Many other lipid nanoparticle-mRNA formulations are in clinical trials for the treatment of infectious diseases, cancer and genetic disorders.
“Many other lipid nanoparticle–mRNA formulations are in clinical trials for the treatment of infectious diseases, cancer and genetic disorders2,4,8,12–14 (Tables 1,2).”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
mRNA-based cellular reprogramming, tissue regeneration and genome editing have shown therapeutic potential in preclinical studies.
“Moreover, mRNA-based cellular reprogramming, tissue regeneration and genome editing have shown therapeutic potential in preclinical studies2,4,8,12–14.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]

Engineering of mRNA molecules and design of lipid nanoparticles have been optimized, contributing to the rapid development and clinical assessment of the two COVID-19 mRNA vaccines.
“To address these concerns, the engineering of mRNA molecules (Box 1) and the design of lipid nanoparticles have been optimized2,4,7–17, which has contributed to the rapid development and clinical assessment15,17 of the two COVID-19 mRNA vaccines, mRNA-1273 (NCT04470427)19,20 and BNT162b2 (NCT04368728)21.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
Self-amplifying RNA has similar basic elements to regular mRNA and a long coding region.
“Compared with regular mRNA, self-amplifying RNA (also termed replicon), which was originally derived from an alphavirus genome, has similar basic elements (5′ cap, 5′ and 3′ untranslated regions, 3′ poly(A) tail) and a long coding region.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
After delivery into the cytoplasm, self-amplifying RNA functions as a translation template for the production of the RNA-dependent RNA polymerase.
“After delivery into the cytoplasm, self-amplifying RNA (positive-strand mRNA) functions as a translation template for the production of the RDRP.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
The coding region of self-amplifying RNA contains sequences for an RNA-dependent RNA polymerase, a promoter and structural viral proteins.
“The coding region contains the sequences for an RNA-dependent RNA polymerase (RDRP), a promoter and structural viral proteins (also known as subgenomic sequence).”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
Replacing the subgenomic sequence of self-amplifying RNA by a gene of interest enables high-level expression of desired proteins.
“Replacing the subgenomic sequence by a gene of interest enables high-level expression of desired proteins.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
Initial replication of self-amplifying RNA leads to negative-strand RNA, which acts as a template for the generation of the positive-strand viral genome.
“The initial replication leads to negative-strand RNA, which acts as template for the generation of the positive-strand viral genome.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
Circular RNA does not have a free 5′ cap or 3′ poly(A) tails and is thus unsusceptible to degradation by nucleases and more stable than linear RNA.
“circRNA does not have a free 5′ cap or 3′ poly(A) tails and is, thus, unsusceptible to degradation by nucleases and more stable than linear RNA.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
Circular RNA is a single-stranded RNA with a closed-loop structure.
“Circular RNA (circRNA) is a single-stranded RNA with a closed-loop structure.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
Circular RNA without a stop codon reduces the frequency of ribosome detachment from the RNA, thereby enabling continuous translation and high protein expression.
“Moreover, circRNA without a stop codon reduces the frequency of ribosome detachment from the RNA, thereby enabling continuous translation and high protein expression.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
Transient replication of self-amplifying RNA generates double-stranded RNA and thus self-amplifying RNA tends to activate innate immune pathways.
“The transient replication generates double-stranded RNA (dsRNA) and, thus, self-amplifying RNA tends to activate innate immune pathways.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
The self-amplification process allows the mass production of virions from limited amounts of virus at infection.
“This self-amplification process allows the mass production of virions from limited amounts of virus at infection.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
Synthetic circular RNA can be made by covalently linking the 3′ and 5′ ends of a linear precursor using enzymatic or chemical methods.
“Synthetic circRNA can be made by covalently linking the 3′ and 5′ ends of a linear precursor using enzymatic or chemical methods.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
The positive-strand self-amplifying RNA serves as a genomic template for RNA-dependent RNA polymerase-mediated replication.
“Moreover, the positive-strand mRNA serves as a genomic template for RDRP-mediated replication.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
Chemical modification of specific nucleotides and chromatographic purification can minimize immunogenicity of RNA and increase translation.
“Similar to linear mRNA, the chemical modification of specific nucleotides and chromatographic purification can minimize immunogenicity of the RNA and increase translation.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
The promoter in the negative-strand RNA is recognized by the RNA-dependent RNA polymerase, leading to transcription of capped subgenomic RNA that encodes structural viral proteins.
“Meanwhile, the promoter in the negative-strand RNA is recognized by the RDRP, leading to the transcription of capped subgenomic RNA that encodes structural viral proteins.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]
Polymers such as polyethyleneimine, protamine and polyaspartamide derivatives are already widely used for mRNA delivery.
“Polymers, such as polyethyleneimine, protamine and polyaspartamide derivatives, are already widely used for mRNA delivery7–17.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [13]

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Lipid nanoparticles for mRNA delivery
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Authors: Uchida, S., Perche, F., Pichon, C., & Cabral, H.
Affiliations: Innovation Center of NanoMedicine (JP)
Centre National de la Recherche Scientifique (FR)
Université d'Orléans (FR)
Corresponding author: Cabral, Horacio
ORCID: Uchida, Satoshi
Perche, Federico
Pichon, Chantal
Cabral, Horacio
Venue: Molecular Pharmaceutics
Publisher: American Chemical Society (ACS)
Published: 2020-08-26
Volume: 17
Issue: 10
Pages: 3654-3684
ISSN: 1543-8384 (ISSN-L)
1543-8392
DOI: 10.1021/acs.molpharmaceut.0c00618
OpenAlex: W3080316114
Cited by: 139
References: 297
Citations by year: 2026: 10 · 2025: 17 · 2024: 26 · 2023: 30 · 2022: 27 · 2021: 24 · 2020: 4
FWCI: 2.03
Type: journal article
Language: en
Open access: green
hal.science
Licence: other-oa
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-045 (stm-asf)
Locations: Molecular Pharmaceutics (publishedVersion)
PubMed (publishedVersion)
HAL (submittedVersion, other-oa)
Funders: Japan Society for the Promotion of Science (18K19901, 20H04524, JP16H03179)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
Keywords: mRNA delivery, nanomedicine, mRNA therapeutics, mRNA stability, mRNA modification, cellular uptake, controlled release, in vivo targeting, clinical translation, immunotherapy, protein replacement therapy
MeSH terms: Animals, Chemical Engineering, Chemistry, Pharmaceutical, Drug Carriers, Drug Stability, Humans, Immunotherapy, RNA, Messenger, Nanomedicine, Nanoparticles, Drug Liberation

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