Discovery of a Novel Amino Lipid That Improves Lipid Nanoparticle Performance through Specific Interactions with mRNA

  title={Discovery of a Novel Amino Lipid That Improves Lipid Nanoparticle Performance through Specific Interactions with mRNA},
  author={Mark Cornebise and Elisabeth Narayanan and Yan Xia and Edward Acosta and Lei Ci and Hillary Koch and Jaclyn Milton and Staci Sabnis and Timothy Salerno and Kerry E. Benenato},
  journal={Advanced Functional Materials},
Lipid nanoparticles (LNPs) are capable of delivering messenger ribonucleic acid (mRNA) efficiently and systemically as a result of both particle composition and architecture. The particle architecture is determined by how the various components interact with one another to establish a stable equilibrium through self‐assembly. The Coulombic attraction between the anionic oligonucleotide cargo and the ionizable amino lipid within the encapsulation media contributes to the coalescence of the… 

The engineering challenges and opportunities when designing potent ionizable materials for the delivery of ribonucleic acids.

How administration route, cellular heterogeneity, uptake pathway, endosomal escape timing, age, sex and threshold effects can change depending on the type of LNP ionizable lipid is discussed.

Lipid nanoparticles for delivery of RNA therapeutics: Current status and the role of in vivo imaging

This review concludes that the development of multiple LNP-based RNA therapeutics is gaining momentum due to its potential in vaccines and therapeutics for various genetic diseases and cancers and imaging techniques can be utilized to evaluate the pharmacokinetics and pharmacodynamics effects.

Lipid Nanoparticle Technologies for Nucleic Acid Delivery: A Nanoarchitectonics Perspective

The latest efforts to develop next‐generation lipid‐based nanoparticles are covered by taking a nanoarchitectonics perspective and the design, nucleic acid encapsulation methods, scalable production, and application prospects are critically analyzed for three classes of lipid‐ based nanoparticles.

mRNA-Loaded Lipid Nanoparticles Targeting Dendritic Cells for Cancer Immunotherapy

A-11-LNP, which was found to be the optimal formulation, induced better transgene expression activity and maturation in DCs and induced clear therapeutic antitumor effects in an E.G7-OVA tumor model compared to two clinically relevant LNP formulations.

Lipid-mRNA nanoparticles landscape for cancer therapy

This review discusses formulation components of mRNA-LNPs, summarizes the latest findings of mRNA cancer therapy, highlights challenges, and offers directions for more effective nanotherapeutics for cancer patients.

Intratumoral delivery of IL-12 and IL-27 mRNA using lipid nanoparticles for cancer immunotherapy.

Tools shaping drug discovery and development

The overview of the biophysical methods in this review is meant to showcase the uses of multiple techniques for different modalities and present recent applications for tackling particularly challenging situations in drug development that can be solved with the aid of fluorescence spectroscopy, nuclear magnetic resonance spectroscopic, atomic force microscopy, and small-angle scattering.

Using nanomaterials to address SARS-CoV-2 variants through development of vaccines and therapeutics

This review examines the existing literature on COVID-19 related nanomaterial applications, including perspective on nanotechnology-based vaccines and therapeutics, and discusses how these tools can be adapted to address new SARS-CoV-2 variants of concern.

Novel mRNA therapy restores GALT protein and enzyme activity in a zebrafish model of classic galactosemia

This study shows that mRNA therapy restores GALT protein and enzyme activity in the CG zebrafish model, and that the zebra fish is a suitable system to test this approach.



Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA

Structure-activity analysis of cholesterol analogues reveals that incorporation of C-24 alkyl phytosterols into LNPs (eLNPs) enhances gene transfection and the length ofAlkyl tail, flexibility of sterol ring and polarity due to -OH group is required to maintain high transfections.

On the Formation and Morphology of Lipid Nanoparticles Containing Ionizable Cationic Lipids and siRNA.

Cryogenic transmission electron microscopy (cryo-TEM) and X-ray evidence is provided that the complexes formed between siRNA and ionizable lipid at pH 4 correspond to tightly packed bilayer structures with siRNA sandwiched between closely apposed monolayers.

Rational design of cationic lipids for siRNA delivery

The best-performing lipid recovered after screening (DLin-KC2-DMA) was formulated and characterized in SNALP and demonstrated to have in vivo activity at siRNA doses as low as 0.01 mg/kg in rodents and 0.1 mg/ kg in nonhuman primates, a substantial improvement over previous reports of in vivo endogenous hepatic gene silencing.

Microfluidic Mixing: A General Method for Encapsulating Macromolecules in Lipid Nanoparticle Systems.

It is shown that LNP-siRNA systems can exhibit progressively more bilayer structure as the proportion of bilayer DSPC lipid is increased, suggesting that the core of LNPs can exhibit a continuum of nanostructures depending on the proportions and structural preferences of component lipids.

Assessing the heterogeneity level in lipid nanoparticles for siRNA delivery: size-based separation, compositional heterogeneity, and impact on bioperformance.

The present results demonstrate the complexity and potential for presence of heterogeneity in LNP-based siRNA drug products and underscores the need for tools that yield a detailed characterization of LNP formulations.

Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo**

A tight correlation between the lipid pK(a) value and silencing of the mouse FVII gene (FVII ED(50) ) was found, with an optimal pK (a) range of 6.2-6.5.

Influence of Cationic Lipid Composition on Gene Silencing Properties of Lipid Nanoparticle Formulations of siRNA in Antigen-Presenting Cells

In vivo results showed that LNP siRNA systems containing DLinKC2-DMA are effective agents for silencing GAPDH in APCs in the spleen and peritoneal cavity following systemic administration.

Encapsulated microRNA by gemcitabine prodrug for cancer treatment.