Strategies for controlling the innate immune activity of conventional and self-amplifying mRNA therapeutics: Getting the message across

Minnaert, An‐Katrien; Vanluchene, Helena; Verbeke, R; Lentacker, Ine; Smedt, Stefaan C. De; Raemdonck, Koen; Sanders, Niek N.

doi:10.1016/j.addr.2021.113900

Cited by 72 publications

(75 citation statements)

References 243 publications

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“…Conventional mRNA has a relatively small size, with 1000–5000 nucleotides [ 21 ], which leads to easier and more effective mRNA encapsulation. Liang et al demonstrated that a conventional mRNA-based vaccine can effectively induce both innate immunity and adaptive responses [ 22 ].…”

Section: Major Types Of Mrna Vaccinementioning

confidence: 99%

Nonviral Delivery Systems of mRNA Vaccines for Cancer Gene Therapy

et al. 2022

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In recent years, the use of messenger RNA (mRNA) in the fields of gene therapy, immunotherapy, and stem cell biomedicine has received extensive attention. With the development of scientific technology, mRNA applications for tumor treatment have matured. Since the SARS-CoV-2 infection outbreak in 2019, the development of engineered mRNA and mRNA vaccines has accelerated rapidly. mRNA is easy to produce, scalable, modifiable, and not integrated into the host genome, showing tremendous potential for cancer gene therapy and immunotherapy when used in combination with traditional strategies. The core mechanism of mRNA therapy is vehicle-based delivery of in vitro transcribed mRNA (IVT mRNA), which is large, negatively charged, and easily degradable, into the cytoplasm and subsequent expression of the corresponding proteins. However, effectively delivering mRNA into cells and successfully activating the immune response are the keys to the clinical transformation of mRNA therapy. In this review, we focus on nonviral nanodelivery systems of mRNA vaccines used for cancer gene therapy and immunotherapy.

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Section: Major Types Of Mrna Vaccinementioning

confidence: 99%

Nonviral Delivery Systems of mRNA Vaccines for Cancer Gene Therapy

et al. 2022

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“…Use of base analogues can confer advantages both by ensuring proper protein folding through modulating, as above, production rate and by rendering mRNA invulnerable towards the cell’s innate immune response to foreign mRNAs [ 214 , 227 ]. Cellular recognition of exogenous mRNA is mediated through interaction of the offending molecule with endosomal Toll-like receptors (TLR) 3,7,8 and 12 which leads to its decay, when endogenous mRNA can escape such mechanisms due to the presence of post-translationally modified bases [ 228 ].…”

Section: Mrna Stability and Modificationsmentioning

confidence: 99%

“…The optimal length is a subject of debate; mammalian mRNAs may carry tails comprised of about 250 adenosines but it is considered that tails longer than 150 nucleotides have protruding parts that escape associating with PABPs. “Naked” mRNA poly(A) tails have a propensity to trigger the cytoplasmic deadenylation complex that can compromise mRNA longevity, hence more prudent sizes have been proposed for therapeutic applications [ 159 , 227 ]. A length of 100 to 120 nucleotides is thought to be ideal, increasing translation efficiency and at the same time contributing to uridine depletion by reducing the relative uridine content of mRNA [ 227 , 240 ].…”

Section: Mrna Stability and Modificationsmentioning

confidence: 99%

“…“Naked” mRNA poly(A) tails have a propensity to trigger the cytoplasmic deadenylation complex that can compromise mRNA longevity, hence more prudent sizes have been proposed for therapeutic applications [ 159 , 227 ]. A length of 100 to 120 nucleotides is thought to be ideal, increasing translation efficiency and at the same time contributing to uridine depletion by reducing the relative uridine content of mRNA [ 227 , 240 ].…”

Section: Mrna Stability and Modificationsmentioning

confidence: 99%

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mRNA Therapeutic Modalities Design, Formulation and Manufacturing under Pharma 4.0 Principles

et al. 2021

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In the quest for a formidable weapon against the SARS-CoV-2 pandemic, mRNA therapeutics have stolen the spotlight. mRNA vaccines are a prime example of the benefits of mRNA approaches towards a broad array of clinical entities and druggable targets. Amongst these benefits is the rapid cycle “from design to production” of an mRNA product compared to their peptide counterparts, the mutability of the production line should another target be chosen, the side-stepping of safety issues posed by DNA therapeutics being permanently integrated into the transfected cell’s genome and the controlled precision over the translated peptides. Furthermore, mRNA applications are versatile: apart from vaccines it can be used as a replacement therapy, even to create chimeric antigen receptor T-cells or reprogram somatic cells. Still, the sudden global demand for mRNA has highlighted the shortcomings in its industrial production as well as its formulation, efficacy and applicability. Continuous, smart mRNA manufacturing 4.0 technologies have been recently proposed to address such challenges. In this work, we examine the lab and upscaled production of mRNA therapeutics, the mRNA modifications proposed that increase its efficacy and lower its immunogenicity, the vectors available for delivery and the stability considerations concerning long-term storage.

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“…Another feature of mRNA as a vaccination tool is its self-adjuvanting property. RNA has been repeatedly reported to curb its own translatability via type I interferon or toll-like receptor (TLR) inducible mechanisms [16][17][18][19][20], thus promoting innate at the expense of adaptive immunity [21,22]. Hence, the use of modified hypoimmunogenic mRNA (e.g., O-methylated cap analogs and chemically modified bases such as pseudouridine) [17], and 5-methyl-cytidine limits the self-adjuvanting property of mRNA enhancing and promotes its translation.…”

Section: Introductionmentioning

confidence: 99%

Co-Delivery of mRNA and pDNA Using Thermally Stabilized Coacervate-Based Core-Shell Nanosystems

et al. 2021

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Co-delivery of different species of protein-encoding polynucleotides, e.g., messenger RNA (mRNA) and plasmid DNA (pDNA), using the same nanocarrier is an interesting topic that remains scarcely researched in the field of nucleic acid delivery. The current study hence aims to explore the possibility of the simultaneous delivery of mRNA (mCherry) and pDNA (pAmCyan) using a single nanocarrier. The latter is based on gelatin type A, a biocompatible, and biodegradable biopolymer of broad pharmaceutical application. A core-shell nanostructure is designed with a thermally stabilized gelatin–pDNA coacervate in its center. Thermal stabilization enhances the core’s colloidal stability and pDNA shielding effect against nucleases as confirmed by nanoparticle tracking analysis and gel electrophoresis, respectively. The stabilized, pDNA-loaded core is coated with the cationic peptide protamine sulfate to enable additional surface-loading with mRNA. The dual-loaded core-shell system transfects murine dendritic cell line DC2.4 with both fluorescent reporter mRNA and pDNA simultaneously, showing a transfection efficiency of 61.4 ± 21.6% for mRNA and 37.6 ± 19.45% for pDNA, 48 h post-treatment, whereas established commercial, experimental, and clinical transfection reagents fail. Hence, the unique co-transfectional capacity and the negligible cytotoxicity of the reported system may hold prospects for vaccination among other downstream applications.

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Strategies for controlling the innate immune activity of conventional and self-amplifying mRNA therapeutics: Getting the message across

Abstract: Graphical abstract

Cited by 72 publications

References 243 publications

Nonviral Delivery Systems of mRNA Vaccines for Cancer Gene Therapy

Nonviral Delivery Systems of mRNA Vaccines for Cancer Gene Therapy

mRNA Therapeutic Modalities Design, Formulation and Manufacturing under Pharma 4.0 Principles

Co-Delivery of mRNA and pDNA Using Thermally Stabilized Coacervate-Based Core-Shell Nanosystems

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