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Tools for translation: non-viral materials for therapeutic mRNA delivery
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In the citing paper
“To maximize translation, the mRNA sequence typically incorporates modified nucleosides, such as pseudouridine, N1-methylpseudouridine or other nucleoside analogues23.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [23]
In the citing paper
“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 [7]
In the citing paper
“These lipids can improve nanoparticle properties, such as particle stability, delivery efficacy, tolerability and biodistribution7,14,17.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [7]
In the citing paper
“Trapped in endosomes, in which the pH is lower than in the extracellular environment, ionizable lipids are protonated and, therefore, become positively charged, which may promote membrane destabilization and facilitate endosomal escape of the nanoparticles7,11,14”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [7]
In the citing paper
“To function in vivo, lipid nanoparticle–mRNA formulations need to overcome multiple extracellular and intracellular barriers7,11 (Fig. 3a).”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [7]
In the citing paper
“In addition to cationic or ionizable lipids, lipid nanoparticle–mRNA formulations typically contain other lipid components, such as phospholipids (for example, phosphatidylcholine and phosphatidylethanolamine), cholesterol or polyethylene glycol (PEG)-functionalized lipids (PEG-lipids)7,14,17.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [7]
In the citing paper
“The pH-sensitivity of ionizable lipids is beneficial for mRNA delivery in vivo, because neutral lipids have less interactions with the anionic membranes of blood cells and, thus, improve the biocompatibility of lipid nanoparticles7,11,14.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [7]
In the citing paper
“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 [7]
In the citing paper
“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 [7]
In the citing paper
“Chemical modifications of specific IVT mRNA nucleotides, such as pseudouridine (ψ) and N1-methylpseudouridine (m1ψ), can reduce innate immune sensing of exogenous mRNA translation2,4,7,182.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [7]
In the citing paper
“Chromatographic purification can remove double-stranded RNA, an analogue of viral genome, in IVT mRNA preparations, diminishing immune activation and increasing translational efficiency2,4,7,183.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [7]
In the citing paper
“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 [7]
In the citing paper
“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 [7]
In the citing paper
“mRNA functions as the bridge between DNA and proteins in eukaryotic cells.[8, 12, 119]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [8]
In the citing paper
“Polyethylenimine (PEI) is one of the most developed cationic polymers [39], but its toxicity has limited the therapeutic applications.[8, 124]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [8]
In the citing paper
“Compared with protein drugs, mRNA can supplement both cytoplasmic and large transmembranic proteins.[8, 119, 120]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [8]
In the citing paper
“Recently, many biomaterials have been developed for mRNA delivery, including lipids and lipid derived materials, polymers, and many others. [8, 39, 120, 124]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [8]
In the citing paper
“Relative to plasmid DNA (pDNA), mRNA possesses temporary bioactivity and functions outside the nucleus, leading to a more controllable protein expression and avoiding the potential insertion of the genome.[8, 119, 120]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [8]
In the citing paper
“For many GARDs, the liver is a preferred organ for mRNA-based PRTs because systemically administrated mRNA vehicles are predominantly trapped by the reticuloendothelial system (RES) in the liver.”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [8]
In the citing paper
“In addition, the interaction between apolipoprotein E (apoE) and biomaterials such as lipid and lipid derived materials facilitates the accumulation in the liver.[8, 18, 34, 39, 59, 120, 121, 124, 164, 165]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [8]
In the citing paper
“Meanwhile, ionizable lipid and lipid derived materials, which acquire positive charges at low pH and become neutral at physiological pH, have been developed for decreasing the toxicity and immunogenicity while retaining the delivery efficiency.[8]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [8]
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“In recent years, many efforts have been made to explore efficient chemical compositions and formulation methods for establishing effective platforms for mRNA delivery [1, 2].”
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BackgroundStructure–Activity Relationship of Ionizable Lipids for siRNA and mRNA Lipid Nanoparticle Design
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“Hajj, K.A.; Whitehead, K.A./2017 [34] Tools for translation: materials for mRNA delivery.”
BackgroundEffective mRNA Delivery by Condensation with Cationic Nanogels Incorporated into Liposomes
Duskunovic, N., Im, S. H., Lee, J. H., & Chung, H. J. (2023) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.3c00089 · Cited by 14
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Non-viral vectors for chimeric antigen receptor immunotherapy
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“There is substantial research being done in the preclinical development of mRNA-based immunotherapies across a multitude of disease types 124,125 .”
Ionizable Lipids with Branched Linkers Enhance the Delivery of mRNA Vaccines
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“…sites, the positive charge of Q IID facilitates interaction with negatively charged fungal cell walls, resulting in enhanced drug retention at the infection site, increasing the fungal membrane disruption, and 90% fungal growth inhibition after efficient loading and release of Fluc [124,140,141].”
Brachyury engineers cardiac repair competent stem cells
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“siRNA-based therapeutics is projected to treat various diseases, target cells, and/or genetic components (Hajj and Whitehead, 2017).”
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“1 3 cellular uptake and delivery efficacy [47].”
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“Efficient mRNA delivery has been the focus of extensive research, which has led to the development of various materials, including lipids, lipid-like compounds, polymers, and protein derivatives [20, 21, 23-30].”
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“It was reported that even a short Poly A tail sequence of around 33 to 34 NT showed high translation efficiency [14] and it was also observed that at least 30–40 adenosines were deemed necessary to inhibit both the 5 ′ to 3 ′ and 3 ′ to 5 ′ mRNA degradation pathways [18].”
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“In order to have the maximummRNA release into the targeted site, the delivery system must have more phospholipid and polyethylene glycol (PEG) than cholesterol and ionizable lipids [333].”
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“In this regard, application of messenger RNA (mRNA), which acts in cytoplasm, is more perspective [3].”
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BackgroundA Chemoinformatic-Guided Synthesis of a Spleen-Expressing mRNA Lipid Nanoparticle Platform
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“89 Ionizable lipids unite within the LNPs and form an electrostatically stable lipoplex by their complexation with mRNA.”
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“However, their use has been linked to liver damage and inflammation resulting from interactions with molecules in the body [68].”
BackgroundBioinspired and bioengineered nucleic acid drug carriers
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“In addition, naked nucleic acid drugs are hydrophilic macromolecules with a high density of negative charges, making them difficult for target cells to take up efficiently [9].”
Lu, Y., Li, Z., Zhu, X., Zeng, Q., Liu, S., & Guan, W. (2025) · International Journal of Nanomedicine · doi:10.2147/ijn.s503780 · Cited by 11
“115 Liposomes therefore protect the active drug from degradation in body fluids and overcome barriers to cellular and tissue absorption.”
Li, L., Luo, M., Zhou, L., Wang, Y., Jiao, Y., Wang, C., Gong, C., Cen, X., & Yao, S. (2025) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2025.125282 · Cited by 11
Diverse nanoparticles deliver mRNA to enhance tumor immunotherapy
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“…(LNPs) are used to encapsulate mRNA drugs to provide protection against degradation, enhance delivery to target cells, reduce toxicity to normal tissues, prolong drug residence time, and improve drug effectiveness. mRNA-LNP therapy holds great promise for the treatment of malignant tumors (19).”
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“Physical technologies, such as gene guns, hydrodynamic delivery, electroporation, microinjection, and microfluidic squeezing, have been exploited for mRNA delivery (26).”
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“These ongoing challenges prevent mRNA from being widely used in biomedicine [47].”
BackgroundGilbert, J., Ermilova, I., Fornasier, M., Skoda, M., Fragneto, G., Swenson, J., & Nylander, T. (2023) · Nanoscale · doi:10.1039/d3nr03308b · Cited by 11
Wojtczak, A., Kasprzyk, R., Warmiński, M., Ubych, K., Kubacka, D., Sikorski, P. J., Jemielity, J., & Kowalska, J. (2021) · Scientific Reports · doi:10.1038/s41598-021-87306-8 · Cited by 11
Applications and challenges of biomaterial mediated mRNA delivery
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Saponin and fluorine-modified polycation as a versatile gene delivery system
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“…of the gene editor protein which can increase safety ) as well as the important role of mRNA-based vaccines for treatment of many diseases [ 59, 60 ] , and especially in the case of vaccines against COVID-19 [ 61 ] , we assessed the potential of PEI-PBA-SAP-F vector for delivery of mRNA into…”
Engineered Silica Nanoparticles for Nucleic Acid Delivery
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“The mRNA is three to four times too large to readily diffuse into cells, and its negative charge electro-statically repulses anionic cell membranes, preventing its uptake (Hajj & Whitehead, 2017).”
BackgroundThe dawn of a new Era: mRNA vaccines in colorectal cancer immunotherapy
Song, J., Zhang, Y., Zhou, C., Zhan, J., Cheng, X., Huang, H., Mao, S., & Zong, Z. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112037 · Cited by 10
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Gao, D., Xu, Z., Li, X., Zhao, Y., Min, Q., Chen, Z., Xu, Q., Tian, Y., Xu, J., & Zhu, J. (2025) · Angewandte Chemie International Edition · doi:10.1002/anie.202505290 · Cited by 11
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“Beyond vaccines, mRNA is being explored for protein-replacement therapy [57], cancer immunotherapy, cellular reprogramming, and gene editing [62–64].”
Natural killer cells in adoptive cell therapy: current landscape of genetic engineering strategies
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“84 Thanks to their safer clinical profile, high transfection efficiency, and cost-effective manufacturing process of clinical grade for non-viral vectors, the number of publications based on non-viral transfection of NK cells has dramatically increased in recent years.”
Success of nano-vaccines against COVID-19: a transformation in nanomedicine
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“5), they convert to an ionized state that mediates effective intracellular delivery via endosomal escape [57,58].”
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Metadata
- Authors
- Hajj, K. A., & Whitehead, K. A.
- Affiliations
- Carnegie Mellon University (US)
- Corresponding author
- Whitehead, Kathryn A.
- Venue
- Nature Reviews Materials
- Published
- 2017-09-12
- Volume
- 2
- Issue
- 10
- ISSN
- 2058-8437 (ISSN-L)
- OpenAlex
- W2754401101
- Cited by
- 799
- References
- 166
- Citations by year
- 2026: 61 · 2025: 122 · 2024: 110 · 2023: 126 · 2022: 124 · 2021: 101 · 2020: 82 · 2019: 40 · 2018: 32 · 2017: 1
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature Reviews Materials (publishedVersion)
- Funders
- Defense Advanced Research Projects Agency (D16AP00143)
- Advanced Research Projects Agency
- 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 › RNA and protein synthesis mechanisms
- Keywords
- mRNA therapeutics, mRNA delivery, synthetic materials, lipid nanoparticles, mRNA vaccines, cancer immunotherapy, in vitro transcribed mRNA
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