Nanoscale platforms for messenger RNA delivery

Li, Bin; Zhang, Xinfu; Dong, Yizhou

doi:10.1002/wnan.1530

Cited by 138 publications

(146 citation statements)

References 130 publications

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“…In the cytoplasm, the immunogenicity concerns of mRNA are minimized by introducing structural modifications to the mRNA (9). Effective mRNA delivery remains a major technical barrier, only successfully overcome by a few approaches, including lipid nanoparticles (LNP), charge-altering releasable transporters (CART), and a few other systems (10).…”

Section: Introductionmentioning

confidence: 99%

Local Delivery ofOx40l,Cd80, andCd86mRNA Kindles Global Anticancer Immunity

et al. 2019

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Localized expression of effector molecules can initiate antitumor responses through engagement of specific receptors on target cells in the tumor microenvironment. These locally induced responses may also have a systemic effect, clearing additional tumors throughout the body. In this study, to evoke systemic antitumor responses, we utilized charge-altering releasable transporters (CART) for local intratumoral delivery of mRNA coding for costimulatory and immune-modulating factors. Intratumoral injection of the CART-mRNA complexes resulted in mRNA expression at the site of administration, transfecting a substantial proportion of tumor-infiltrating dendritic cells, macrophages, and T cells in addition to the tumor cells, resulting in a local antitumor effect. Using a twotumor model, we further show that mRNA therapy locally administered to one tumor stimulated a systemic antitumor response, curing both tumors. The combination of Ox40l-, Cd80-, and Cd86-encoding mRNA resulted in the local upregulation of proinflammatory cytokines, robust local T-cell activation, and migration of immune cells to local draining lymph node or to an anatomically distant tumor. This approach delayed tumor growth, facilitated tumor regression, and cured tumors in both A20 and CT26 tumor models. These results highlight mRNA-CART therapy as a viable approach to induce systemic antitumor immunity from a single localized injection.Significance: The mRNA-CART system is a highly effective delivery platform for delivering immunostimulatory genes into the tumor microenvironment for potential therapeutic development.

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Section: Introductionmentioning

confidence: 99%

Local Delivery ofOx40l,Cd80, andCd86mRNA Kindles Global Anticancer Immunity

et al. 2019

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“…12, 18, 21, 22, 25, 26, 35 mRNA-based therapy possesses advantages over other nucleic acid-based approaches due to its endogenous translation process in the cytosol and no potential risk of genome mutagenesis. 15,28,32 However, the instability and insufficient translatability of mRNA remain a limitation to achieving maximized therapeutic windows.…”

Section: Introductionmentioning

confidence: 99%

Lipid Polymer Hybrid Nanomaterials for mRNA Delivery

Zhao

Zhang

et al. 2018

Cel. Mol. Bioeng.

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Introduction In the past decade, messenger RNA (mRNA) has been extensively explored in a wide variety of biomedical applications. However, efficient delivery of mRNA is still one of the key challenges for its broad applications in the clinic. Recently, lipid polymer hybrid nanoparticles (LPNs) are evolving as a promising class of biomaterials for RNA delivery, which integrate the physicochemical properties of both lipids and polymers. We previously developed an N1,N3,N5-tris(2-aminoethyl)benzene-1,3,5-tricarboxamide (TT) derived lipid-like nanomaterial (TT3-LLN) which was capable of effectively delivering multiple types of mRNA. In order to further improve the delivery efficiency of TT3-LLN, in this study, we focused on studying the effects of incorporating different polymers on establishing LPNs and aimed to develop an optimized lipid polymer hybrid nanomaterial for efficient mRNA delivery. Methods We incorporated a series of biodegradable and biocompatible polymer materials into the formulation of TT3-LLNs to develop LPNs. mRNA delivery efficiency of different LPNs were evaluated and a systematic orthogonal optimization was further carried out. Results Our data indicate that PLGA4 (MW 24,000–38,000 g/mol) dramatically increased delivery efficiency of TT3-LLNs in comparison to other polymers. Further optimization identified PLGA4–7 LPNs (PLGA:mRNA=9:1, mass ratio; TT3:DOPE:Cholesterol:DMG-PEG2000=25:25:45:0.75, molar ratio) as a lead formulation, which displayed significantly enhanced delivery of two types of mRNA in three different human cell lines as compared with TT3-LLNs. Conclusions Results from this study potentially provide new insights into developing LPNs for mRNA based therapeutics.

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“…Substantial attention has been placed on the development of novel ionizable lipids and formulations, with improvements in cellular uptake, endosomal release, potency, and biodegradability. [55][56][57] The combinations of all of these areas for optimization are near limitless, and success within any of these parameters can allow for beneficial effects and can provide novel approaches for vaccines to successfully prevent disease.…”

Section: Biotech and Industrial Perspectivesmentioning

confidence: 99%

The promise of mRNA vaccines: a biotech and industrial perspective

Jackson¹,

et al. 2020

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mRNA technologies have the potential to transform areas of medicine, including the prophylaxis of infectious diseases. The advantages for vaccines range from the acceleration of immunogen discovery to rapid response and multiple disease target manufacturing. A greater understanding of quality attributes that dictate translation efficiency, as well as a comprehensive appreciation of the importance of mRNA delivery, are influencing a new era of investment in development activities. The application of translational sciences and growing early-phase clinical experience continue to inform candidate vaccine selection.Here we review the state of the art for the prevention of infectious diseases by using mRNA and pertinent topics to the biotechnology and pharmaceutical industries.npj Vaccines (2020) 5:11 ; https://doi.

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Nanoscale platforms for messenger RNA delivery

Cited by 138 publications

References 130 publications

Local Delivery ofOx40l,Cd80, andCd86mRNA Kindles Global Anticancer Immunity

Local Delivery ofOx40l,Cd80, andCd86mRNA Kindles Global Anticancer Immunity

Lipid Polymer Hybrid Nanomaterials for mRNA Delivery

The promise of mRNA vaccines: a biotech and industrial perspective

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