Table 4 Strategies for improving mRNA translation efficiency
From: The use of RNA-based treatments in the field of cancer immunotherapy
Strategy | Advantages | Disadvantages | Immunogenicity | Efficacy | Safety | Stability | Description | Reference |
|---|---|---|---|---|---|---|---|---|
Five-prime cap (5' Cap) modification | Increase translation efficiency, reduce innate immune response | Expensive and time-consuming to synthesize | Low to moderate | High | Safe | Stable | Addition of a modified 5' cap to the mRNA molecule to improve translation efficiency | [323] |
Optimization of UTRs | Improve translation initiation and elongation | May not work for all mRNA sequences | Low to moderate | High | Safe | Stable | Alteration of the 5' and 3' untranslated regions to optimize mRNA translation | [324] |
Codon optimization of open reading frame (ORF) | Improve translation efficiency by selecting optimal codons for the target protein | May not be effective for all mRNA sequences, codon optimization can be difficult for complex proteins | Low to moderate | High | Safe | Stable | Modification of the mRNA sequence to include codons that are optimal for the translation of the target protein | [325] |
Poly(A) tail modification | Increase translation efficiency and stability of mRNA | Can be time-consuming and costly to synthesize | Low to moderate | High | Safe | Stable | Addition of a modified poly(A) tail to the mRNA to improve stability and translation efficiency | [326] |
Nucleoside-modified mRNA | Increase stability and translational efficiency of mRNA | May increase immunogenicity | Low to moderate | High | Safe | Stable | Substitution of natural nucleotides with modified nucleotides to enhance stability and translation efficiency of the mRNA | [327] |
Purification of in vitro transcribed mRNA (IVT-mRNA) | Improve purity and quality of mRNA for translation | Can be time-consuming and expensive | Low to moderate | High | Safe | Stable | Purification of mRNA using chromatography to remove impurities and increase mRNA quality | [328] |
Utilizing the impact of type I IFN | Enhance the immunostimulatory effect of mRNA vaccines | Can be difficult to predict the effect of IFN on specific mRNA vaccines | Low to moderate | High | Safe | Stable | Addition of type I IFN to mRNA vaccines to increase their immunostimulatory effect | [329] |
Type 1 cap (Type 1 Cap-0, Type 1 Cap-1) | Improved stability and increased translation efficiency | Can be difficult to synthesize and may increase cost | Low to moderate | High | Safe | Stable | Type 1 Cap-0 and Type 1 Cap-1 modifications of the mRNA cap structure to enhance stability and translation efficiency | [330] |
Modification of regulatory elements | Increase mRNA stability and translation | Can be difficult to predict the effect on specific mRNA vaccines | Low to moderate | High | Safe | Stable | Modification of regulatory elements such as miRNA binding sites, AU-rich elements, or splice sites to enhance mRNA stability and translation | [331] |
Cell-specific targeting of mRNA | Increase mRNA uptake by specific cells and improve translation | May require additional modifications or targeting agents | Low to moderate | High | Safe | Stable | Incorporation of targeting moieties such as aptamers or antibodies to improve cell-specific uptake and translation of mRNA | [332] |
Combination of strategies | Potential for synergistic effects and increased efficacy | May increase complexity and cost of mRNA synthesis | Low to moderate | High | Safe | Stable | Combination of two or more strategies to enhance mRNA translation efficiency and efficacy | [333] |
Use of modified ribonucleoside analogs | Improve stability and translational efficiency | May increase cost of synthesis | Low to moderate | High | Safe | Stable | Substitution of ribonucleosides with modified analogs to increase mRNA stability and translation efficiency | [334] |
Use of optimized mRNA 3' UTRs | Improve translation efficiency and mRNA stability | May not work for all mRNA sequences | Low to moderate | High | Safe | Stable | Modification of the 3' untranslated region (UTR) to improve mRNA stability and translation efficiency | [77] |
Use of small molecule modulators | Improve mRNA translation through regulation of key signaling pathways | May have off-target effects and safety concerns | Low to moderate | High | Safe | Stable | Identification of small molecules that regulate signaling pathways involved in mRNA translation, to improve efficiency and stability | [335] |
Use of exogenous factors | Improve mRNA stability and translation efficiency through the addition of exogenous factors | May be difficult to identify optimal factors and may increase cost of synthesis | Low to moderate | High | Safe | Stable | Addition of exogenous factors such as chaperones or translation initiation factors to improve mRNA stability and translation efficiency | [336] |
Use of self-amplifying mRNA | Increase mRNA stability and translation efficiency through self-amplification | May require additional modifications and increased cost of synthesis | Low to moderate | High | Safe | Stable | Incorporation of self-amplifying mRNA sequences to improve mRNA stability and translation efficiency | [337] |
Use of ribosome engineering | Improve mRNA translation by optimizing the function of ribosomes | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Modification of ribosomes to improve translation efficiency and efficacy of mRNA vaccines | [338] |
Use of circular mRNA | Improve mRNA stability and translational efficiency | May require additional modifications and increase the cost of mRNA synthesis | Low to moderate | High | Safe | Stable | Circularization of mRNA to increase its stability and translational efficiency | [339] |
Use of microRNA-mediated control | Improve mRNA stability and translation through regulation by microRNAs | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Incorporation of microRNA binding sites into the mRNA to regulate its stability and translation efficiency | [340] |
Use of non-coding RNAs | Improve mRNA stability and translation through regulation by non-coding RNAs | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Incorporation of non-coding RNAs such as long non-coding RNAs or circular RNAs to regulate mRNA stability and translation efficiency | [341] |
Use of modified mRNA 5' cap structures | Improve mRNA stability and translation efficiency | May increase the complexity and cost of mRNA synthesis | Low to moderate | High | Safe | Stable | Modification of the mRNA 5' cap structure to improve its stability and translation efficiency | [342] |
Use of riboswitches | Improve mRNA translation by regulating its stability and translation efficiency through riboswitches | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Incorporation of riboswitches into the mRNA to regulate its stability and translation efficiency | [343] |
Use of viral vectors for mRNA delivery | Increase mRNA stability and improve its delivery to target cells | May increase safety concerns and require additional modifications for clinical use | Low to moderate | High | Safe | Stable | Use of viral vectors for mRNA delivery to increase its stability and improve its delivery to target cells | [344] |
Use of protease-resistant mRNA | Improve mRNA stability and translation efficiency by increasing resistance to degradation | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Modification of the mRNA to increase its resistance to proteases and improve its stability and translation efficiency | [345] |
Use of hybrid mRNA molecules | Improve mRNA stability and translation efficiency by incorporating features of different mRNA types | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Hybridization of different types of mRNA to improve their stability and translation efficiency | [346] |
Use of non-natural amino acids | Improve mRNA translation by incorporating non-natural amino acids | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Incorporation of non-natural amino acids into the mRNA to improve its translation efficiency | [347] |
Use of nanoparticle-based delivery systems | Improve mRNA stability and delivery to target cells through the use of nanoparticle-based delivery systems | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Use of nanoparticle-based delivery systems for mRNA to improve its stability and delivery to target cells | [285] |
Use of RNA–protein complexes | Improve mRNA stability and translation efficiency by incorporating RNA–protein complexes | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Incorporation of RNA–protein complexes into the mRNA to improve its stability and translation efficiency | [348] |
Use of mRNA fragments | Improve mRNA stability and translation efficiency by using shorter mRNA fragments | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Use of shorter mRNA fragments to improve their stability and translation efficiency | [349] |
Use of RNA editing | Improve mRNA translation by editing the mRNA sequence to optimize its translation | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Editing of the mRNA sequence to improve its translation efficiency and efficacy | [120] |
Use of RNA interference (RNAi) | Improve mRNA translation and stability through gene silencing by RNAi | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Use of RNAi to silence genes that interfere with mRNA stability and translation | [156] |
Use of translational enhancers | Improve mRNA translation by incorporating translational enhancers | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Incorporation of translational enhancers to improve mRNA translation efficiency | [350] |
Use of RNA-binding proteins | Improve mRNA stability and translation efficiency by incorporating RNA-binding proteins | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Incorporation of RNA-binding proteins to improve mRNA stability and translation efficiency | [351] |
Use of modified nucleotides | Improve mRNA stability and translation efficiency by incorporating modified nucleotides | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Incorporation of modified nucleotides to improve mRNA stability and translation efficiency | [120] |
Use of RNA aptamers | Improve mRNA stability and translation efficiency by incorporating RNA aptamers | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Incorporation of RNA aptamers to improve mRNA stability and translation efficiency | [152] |
Use of RNA secondary structures | Improve mRNA stability and translation efficiency by incorporating RNA secondary structures | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Incorporation of RNA secondary structures to improve mRNA stability and translation efficiency | [352] |
Use of optimized UTRs | Improve mRNA translation by optimizing UTRs for efficient translation | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Optimization of UTRs to improve mRNA translation efficiency | [77] |
Use of modified poly(A) tails | Improve mRNA stability and translation efficiency by incorporating modified poly(A) tails | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Incorporation of modified poly(A) tails to improve mRNA stability and translation efficiency | [326] |
Use of codon optimization | Improve mRNA translation by optimizing codon usage for efficient translation | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Optimization of codon usage to improve mRNA translation efficiency | [353] |
Use of 5’ cap modification | Improve mRNA stability and translation efficiency by modifying the 5’ cap structure | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Modification of the 5’ cap structure to improve mRNA stability and translation efficiency | [354] |
Use of synthetic mRNAs | Generate synthetic mRNAs for improved translation and stability | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Use of synthetic mRNAs for improved translation and stability | [162] |
Use of in vitro transcription (IVT) | Improve mRNA quality and yield through IVT | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Use of IVT for improved mRNA quality and yield | [98] |
Use of type I interferons (IFNs) | Enhance mRNA immunogenicity and efficacy through the use of type I IFNs | May increase immunogenicity and require additional modifications and increase the complexity of mRNA synthesis | High | High | Safe | Stable | Use of type I IFNs to enhance mRNA immunogenicity and efficacy | [104] |
Use of lipid nanoparticles | Improve mRNA stability and delivery to target cells through the use of lipid nanoparticles | May require additional modifications and increase the complexity of mRNA synthesis | Low to moderate | High | Safe | Stable | Use of lipid nanoparticles for mRNA delivery to improve its stability and delivery to target cells | [355] |