Lipid nanoparticle mRNA systems containing high levels of sphingomyelin engender higher protein expression in hepatic and extra-hepatic tissues

Chander, Nisha; Basha, Genc; Cheng, Miffy H. Y.; Witzigmann, Dominik; Cullis, Pieter R.

doi:10.1016/j.omtm.2023.06.005

Cited by 34 publications

(13 citation statements)

References 39 publications

(47 reference statements)

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“…The efficiency of LNPs prepared from a mixture of the two mRNAs and the mixture of H and L LNPs could be compared, and the difference in t 1/2 between the two studies might arise from this. Seventh, the lipid composition, lipid ratio, or buffer conditions are important parameters that could change the physicochemical properties of LNP . We believe that changes in these parameters will affect the pharmacokinetic profile.…”

Section: Limitationsmentioning

confidence: 99%

“…Seventh, the lipid composition, lipid ratio, or buffer conditions are important parameters that could change the physicochemical properties of LNP. 50 We believe that changes in these parameters will affect the pharmacokinetic profile. A complete study of the effect of physicochemical properties of LNP on the pharmacokinetic profile can be performed.…”

Section: Limitationsmentioning

confidence: 99%

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Pharmacokinetic Analyses of a Lipid Nanoparticle-Encapsulated mRNA-Encoded Antibody against Rift Valley Fever Virus

Wang,

Zhu,

2024

Mol. Pharmaceutics

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Rift Valley fever virus (RVFV) could cause an emergency illness characterized by fever, muscle pain, and even death in humans or ruminants. However, there are no approved antiviral drugs that prevent or treat RVFV infection. While therapeutic antibodies have shown promising potential for prevention or treatment in several studies, many studies are ongoing, especially in the field of infectious diseases. Among these studies, the mRNA-LNP platform shows great potential for application, following the COVID-19 pandemic. Previously, we have obtained a neutralizing antibody against RVFV, which was named A38 protein and verified to have a high binding and neutralization ability. In this study, we aimed to identify an effectively optimized sequence and expressed the prioritized mRNA-encoded antibody in vitro. Notably, we effectively expressed mRNA-encoded protein and used the mRNA-LNP platform to generate A38-mRNA-LNP. Pharmacokinetic experiments were conducted in vivo and set up in two groups of mRNA-A38 group and A38 protein group, which were derived from mRNA-LNP and plasmid DNA-expressed proteins, respectively. A38-mRNA-LNPs were administrated by intramuscular injection, A38 proteins were administrated by intravenous administration, and their unique ability to maintain long-lasting protein concentrations by mRNA-encoded protein was demonstrated with the mRNA-encoded protein providing a longer circulating half-life compared to injection of the free A38 protein. These preclinical data on the mRNA-encoded antibody highlighted its potential to prevent infectious diseases in the future.

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Section: Limitationsmentioning

confidence: 99%

Section: Limitationsmentioning

confidence: 99%

Pharmacokinetic Analyses of a Lipid Nanoparticle-Encapsulated mRNA-Encoded Antibody against Rift Valley Fever Virus

Wang,

Zhu,

2024

Mol. Pharmaceutics

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“… 60 LNPs with a high molar proportion of the helper lipid N-(hexadecanoyl)-sphing-4-enine-1-phosphocholine (egg sphingomyelin, ESM) significantly enhanced gene expression in the spleen, compared to mRNA-LNPs with a lower proportion of DSPC. 61 Furthermore, the combination of DODAP and DOPE in LNPs has shown spleen specificity for successful pDNA delivery, targeting complement C3 receptors 62 Synthesis and optimization of ILs. A report showed that the optimal LNPs formulation was identified through orthogonal optimization with the rational design and combinatorial synthesis of esterase-triggered decationizable quaternium lipid-like molecules (lipidoids).…”

Section: Organ-selective Lnps As Delivery Platforms For Nucleic Acidsmentioning

confidence: 99%

Optimized lipid nanoparticles (LNPs) for organ-selective nucleic acids delivery in vivo

Zhang,

Yin,

et al. 2024

iScience

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“…Phospholipids are now designated as "helper" lipid in the LNP system due to its role in nucleic acid encapsulation and stable particle formation, influencing in vivo delivery efficacy. Remarkably, recent research has unveiled that an increased proportion of phospholipids can enhance mRNA delivery efficacy both in vitro and in vivo, particularly when eff sphingomyelin (ESM) substitutes DSPC 23 .…”

Section: Introductionmentioning

confidence: 99%

“…Phospholipids are now designated as “helper” lipid in the LNP system due to its role in nucleic acid encapsulation and stable particle formation, influencing in vivo delivery efficacy. Remarkably, recent research has unveiled that an increased proportion of phospholipids can enhance mRNA delivery efficacy both in vitro and in vivo , particularly when eff sphingomyelin (ESM) substitutes DSPC 23 . Nonetheless, DSPC tends to favor bilayer structures, resulting in LNP formation with bilayer bleb-like structures under stressful conditions 24 or when elevated DSPC quantities are employed 25 .…”

Section: Introductionmentioning

confidence: 99%

Dual Ethanolamine Head Groups in Ionizable Lipids Facilitate Phospholipid-free Stable Nanoparticle Formulation for Augmented and Safer mRNA Delivery

Lu,

Jiang,

et al. 2023

Preprint

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The accelerated advent of mRNA-based therapeutics and vaccines, highlighted by the battle against SARS-CoV-2, underscores the urgency to refine lipid nanoparticles (LNPs) for efficient mRNA delivery. In this work, we introduce a novel series of ionizable lipids characterized by double ethanolamine head groups, significantly amplifying mRNA binding affinity. A succinct three-component formulation is subsequently delineated, obviating the conventional dependency on phospholipids inherent in traditional four-component LNPs. Intriguingly, this formulation enables particle formation under neutral pH conditions, a notable departure from the acidic milieu traditionally required, attributable to the enhanced nonionic interactions predominating in mRNA encapsulation. The resultant particles exhibit exceptional stability, superior mRNA encapsulation efficiency, and maintain robust delivery efficacy. When deployed as a vaccine platform, the formulation elicited pronounced humoral and T-cell immune responses, concurrently exhibiting a favorable toxicity profile with a reduced induction of pro-inflammatory cytokines such as IL-6. Our exploration suggests that by fine-tuning the non-electrostatic interactions between the ionizable lipid and mRNA, the dynamics of particle formation can be considerably divergent from the prevailing paradigms of mRNA-LNP formation, hinting at a broader horizon for lipid optimization within the realm of mRNA delivery systems.

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Lipid nanoparticle mRNA systems containing high levels of sphingomyelin engender higher protein expression in hepatic and extra-hepatic tissues

Cited by 34 publications

References 39 publications

Pharmacokinetic Analyses of a Lipid Nanoparticle-Encapsulated mRNA-Encoded Antibody against Rift Valley Fever Virus

Pharmacokinetic Analyses of a Lipid Nanoparticle-Encapsulated mRNA-Encoded Antibody against Rift Valley Fever Virus

Optimized lipid nanoparticles (LNPs) for organ-selective nucleic acids delivery in vivo

Dual Ethanolamine Head Groups in Ionizable Lipids Facilitate Phospholipid-free Stable Nanoparticle Formulation for Augmented and Safer mRNA Delivery

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