A novel mechanism for the loss of mRNA activity in lipid nanoparticle delivery systems

Packer, Meredith; Gyawali, Dipendra; Yerabolu, Ravikiran; Schariter, Joseph; White, Phil

doi:10.1038/s41467-021-26926-0

Cited by 112 publications

(105 citation statements)

References 30 publications

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“…Later, scientists developed ionizable LNPs to ameliorate this side effect. However, a recent study showed that these ionizable lipids may include impurities, leading to a loss of mRNA activity, while these impurities are difficult to identify with the traditional techniques [ 186 ]. In addition, due to some shortcomings of the LNPs, such as easy oxidation and degradation, nonuniform preparation protocols, and high recurrence rate, large-scale industrial production has been difficult to achieve [ 187 ].…”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

Nonviral Delivery Systems of mRNA Vaccines for Cancer Gene Therapy

et al. 2022

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“…Remarkably, authors showed that stability was protected upon freeze-thaw cycles when cryoprotectants such as sucrose or trehalose [93]-two excipients used in the marketed vaccines-were used. In this regard, more recently, a novel class of mRNA reactivity that leads to loss of activity has been reported: the formation of mRNA-LNP adducts though the covalent union between some reactive lipids and the nucleobase [24,94]. It is also worth noting that mRNA could potentially have more stability issues than siRNA, as it is a longer and more complex molecule.…”

Section: Stability Considerationsmentioning

confidence: 99%

The Potential of Nanomedicine to Unlock the Limitless Applications of mRNA

Taina-González

Fuente

2022

Pharmaceutics

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The year 2020 was a turning point in the way society perceives science. Messenger RNA (mRNA) technology finally showed and shared its potential, starting a new era in medicine. However, there is no doubt that commercialization of these vaccines would not have been possible without nanotechnology, which has finally answered the long-term question of how to deliver mRNA in vivo. The aim of this review is to showcase the importance of this scientific milestone for the development of additional mRNA therapeutics. Firstly, we provide a full description of the marketed vaccine formulations and disclose LNPs’ pharmaceutical properties, including composition, structure, and manufacturing considerations Additionally, we review different types of lipid-based delivery technologies currently in preclinical and clinical development, namely lipoplexes and cationic nanoemulsions. Finally, we highlight the most promising clinical applications of mRNA in different fields such as vaccinology, immuno-oncology, gene therapy for rare genetic diseases and gene editing using CRISPR Cas9.

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“…They constitute an integral part of the mandatory quality control as well as the isolation of high purity intermediates required for products whose synthesis is performed serially. It must be highlighted that in mRNA production, utmost purity of the final product is not only a safety issue, but also a matter of therapeutical efficacy and shelf-life longevity, since contaminants can compromise both shelf-life of the finalized product as well as illicit unwanted immune responses [ 85 , 86 , 87 ]…”

Section: Analytical Approachesmentioning

confidence: 99%

“…Advances in biotechnology require the development of state-of-the-art analytical techniques to ensure that LNP-encapsulated mRNAs are QC-labeled and tested to ensure their safety and efficacy. Modern techniques including liquid (LC), or gas chromatography (GC) and mass spectrometry (MS) are therefore being applied to analyze lipid and mRNA attributes or to detect and quantify lipid impurities [ 86 ].…”

Section: Analytical Approachesmentioning

confidence: 99%

“…In this case, the product could benefit from “tighter” encapsulation methods that will act exclusively towards water molecules, keeping the payload “dry” and intact. Recently, another vulnerability has been reported that concerns the interactions between lipids used in LNP production and the mRNA payload, yields a non-functional product [ 86 ]. The interaction pertains to tertiary amine containing lipids and can result in lipid-mRNA adduct formation that can escape common analytic procedures.…”

Section: Storage Considerationsmentioning

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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A novel mechanism for the loss of mRNA activity in lipid nanoparticle delivery systems

Cited by 112 publications

References 30 publications

Nonviral Delivery Systems of mRNA Vaccines for Cancer Gene Therapy

Nonviral Delivery Systems of mRNA Vaccines for Cancer Gene Therapy

The Potential of Nanomedicine to Unlock the Limitless Applications of mRNA

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

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