DOPC <i>versus</i> DOPE as a helper lipid for gene-therapies: molecular dynamics simulations with DLin-MC3-DMA

Ermilova, Inna; Swenson, Jan

doi:10.1039/d0cp05111j

Cited by 52 publications

(59 citation statements)

References 89 publications

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“…The extents of MC3 accumulation in MC3/POPC binary bilayers are less pronounced than that of neutral KC2 in KC2/POPC binary bilayers, whereas the MC3 accumulation at 15 mol% MC3 in MC3/POPE bilayer (MC3-PE85) is comparable to KC2 accumulation in KC2/POPC bilayers (in between those in KC2-PC90 and KC2-PC80). The observed less pronounced accumulation of MC3 than KC2 can be attributed to MC3's structure, where carbonyl oxygen atoms in MC3 head group can interact with the PE head group or glycerol backbone in PC/PE, which can hinder MC3 accumulation in the bilayer center (Ermilova and Swenson10 and Fig.1)The accumulation of MC3 was not observed in the previous study of Ermilova and Swenson 10 with MC3/DOPC and MC3/DOPE binary bilayers. We attribute the observed MC3 accumulation in Case 2 to the difference in the force fields between our work and theirs.…”

mentioning

confidence: 71%

“…To illustrate this new feature, we have built and simulated all systems of two previous simulation studies, Ramezanpour et al 9 and Ermilova and Swenson. 10 As another more practical illustration to demonstrate Membrane Builder's capability to build a realistic LNP patch, we built and simulated KC2-and MC3-based LNP membranes with very high cholesterol and ionizable cationic lipids together with 2 mol% PEG-lipids.…”

Section: Discussionmentioning

confidence: 99%

“…5c), indicating that MC3 induces negative curvature with POPC, which is likely due to the interactions between carbonyl oxygen in MC3 and the glycerol backbone in POPC. 10 Opposite to the variation in MC3/POPC, increasing MC3 concentration makes become more positive in MC3/POPE binary bilayer due to the accumulation of MC3 in the bilayer center, rendering the POPE monolayer curvature less negative and thus the entire system becomes more stable. Similarly to KC2H, are not sensitive to MC3H concentration both in MC3H/POPC and MD3H/POPE binary bilayers.…”

Section: Effects Of Ionizable Cationic Lipids and Peg-lipids On Membrane Curvaturementioning

confidence: 99%

“…More recently, Ermilova and Swenson performed all-atom MD simulations of neutral MC3 in dioleoyl-phosphatidylcholine (DOPC) or dioleoyl-phosphatidylethanolamine (DOPE) bilayers. 10 The main observation was that neutral MC3 head groups at 5 and 15 mol% positioned at the DOPE bilayer-water interface due to strong interactions between DOPE head groups and MC3 head groups and tails, whereas there are no such interactions between MC3 and DOPC. Note that these systems are relatively simple in that LNP formulations generally contain very high concentrations of CHOL and ionizable cation lipids together with 1-5 mol% PEG-lipids.…”

Section: Introductionmentioning

confidence: 99%

“…20 As a first illustration, we have built and simulated all systems of the aforementioned two simulation studies. 9,10 In addition, to demonstrate Membrane Builder's capability to build a realistic LNP patch, we built and simulated KC2-or MC3-containing LNP membranes with high concentration of CHOL (47 mol%) and ionizable cationic lipids (40 mol%) together with 2 mol% PEG-lipids.…”

Section: Introductionmentioning

confidence: 99%

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CHARMM-GUI Membrane Builder for Lipid Nanoparticles with Ionizable Cationic Lipids and PEGylated Lipids

Park

Choi

Kim

et al. 2021

Preprint

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A lipid nanoparticle (LNP) formulation is a state-of-the-art delivery system for genetic drugs such as DNA, mRNA, and siRNA, which is successfully applied to COVID-19 vaccines and gains tremendous interest in therapeutic applications. Despite its importance, a molecular-level understanding of the LNP structures and dynamics is still lacking, which makes a rational LNP design almost impossible. In this work, we present an extension of CHARMM-GUI Membrane Builder to model and simulate all-atom LNPs with various (ionizable) cationic lipids and PEGylated lipids (PEG-lipids). These new lipid types can be mixed with any existing lipid types with or without a biomolecule of interest, and the generated systems can be simulated using various molecular dynamics engines. As a first illustration, we considered model LNP membranes with DLin-KC2-DMA (KC2) or DLin-MC3-DMA (MC3) without PEG-lipids. The results from these model membranes are consistent with those from the two previous studies albeit with mild accumulation of neutral MC3 in the bilayer center. To demonstrate Membrane Builder's capability of building a realistic LNP patch, we generated KC2- or MC3-containing LNP membranes with high concentrations of cholesterol and ionizable cationic lipids together with 2 mol% PEG-lipids. We observe that PEG-chains are flexible, which can be more preferentially extended laterally in the presence of cationic lipids due to the attractive interactions between their head groups and PEG oxygen. The presence of PEG-lipids also relaxes the lateral packing in LNP membranes, and the area compressibility modulus (KA) of LNP membranes with cationic lipids fit into typical KA of fluid-phase membranes. Interestingly, the interactions between PEG oxygen and head group of ionizable cationic lipids induce a negative curvature. We hope that this LNP capability in Membrane Builder can be useful to better characterize various LNPs with or without genetic drugs for a rational LNP design.

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mentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Effects Of Ionizable Cationic Lipids and Peg-lipids On Membrane Curvaturementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

CHARMM-GUI Membrane Builder for Lipid Nanoparticles with Ionizable Cationic Lipids and PEGylated Lipids

Park

Choi

Kim

et al. 2021

Preprint

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Nano Plasma Membrane Vesicle‐Lipid Nanoparticle Hybrids for Enhanced Gene Delivery and Expression

Alter,

Lotter,

Puligilla

et al. 2024

Adv Healthcare Materials

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Lipid nanoparticles (LNPs) have emerged as the leading nonviral nucleic acid (NA) delivery system, gaining widespread attention for their use in COVID‐19 vaccines. They are recognized for their efficient NA encapsulation, modifiability, and scalable production. However, LNPs face efficacy and potency limitations due to suboptimal intracellular processing, with endosomal escape efficiencies (ESE) below 2.5%. Additionally, up to 70% of NPs undergo recycling and exocytosis after cellular uptake. In contrast, cell‐derived vesicles offer biocompatibility and high‐delivery efficacy but are challenging to load with exogenous NAs and to manufacture at large‐scale. To leverage the strengths of both systems, a hybrid system is designed by combining cell‐derived vesicles, such as nano plasma membrane vesicles (nPMVs), with LNPs through microfluidic mixing and subsequent dialysis. These hybrids demonstrate up to tenfold increase in ESE and an 18‐fold rise in reporter gene expression in vitro and in vivo in zebrafish larvae (ZFL) and mice, compared to traditional LNPs. These improvements are linked to their unique physico‐chemical properties, composition, and morphology. By incorporating cell‐derived vesicles, this strategy streamlines the development process, significantly enhancing the efficacy and potency of gene delivery systems without the need for extensive screening.

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Impact of administration routes and dose frequency on the toxicology of SARS-CoV-2 mRNA vaccines in mice model

Ahn,

Lee,

Roh

et al. 2024

Arch Toxicol

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The increasing use of SARS-CoV-2 mRNA vaccines has raised concerns about their potential toxicological effects, necessitating further investigation to ensure their safety. To address this issue, we aimed to evaluate the toxicological effects of SARS-CoV-2 mRNA vaccine candidates formulated with four different types of lipid nanoparticles in ICR mice, focusing on repeated doses and administration routes. We conducted an extensive analysis in which mice received the mRNA vaccine candidates intramuscularly (50 μg/head) twice at 2-week intervals, followed by necropsy at 2 and 14 dpsi (days post-secondary injection). In addition, we performed a repeated dose toxicity test involving three, four, or five doses and compared the toxicological outcomes between intravenous and intramuscular routes. Our findings revealed that all vaccine candidates significantly induced SARS-CoV-2 spike protein-specific IgG and T cell responses. However, at 2 dpsi, there was a notable temporary decrease in lymphocyte and reticulocyte counts, anemia-related parameters, and significant increases in cardiac damage markers, troponin-I and NT-proBNP. Histopathological analysis revealed severe inflammation and necrosis at the injection site, decreased erythroid cells in bone marrow, cortical atrophy of the thymus, and increased spleen cellularity. While most toxicological changes observed at 2 dpsi had resolved by 14 dpsi, spleen enlargement and injection site damage persisted. Furthermore, repeated doses led to the accumulation of toxicity, and different administration routes resulted in distinct toxicological phenotypes. These findings highlight the potential toxicological risks associated with mRNA vaccines, emphasizing the necessity to carefully consider administration routes and dosage regimens in vaccine safety evaluations, particularly given the presence of bone marrow and immune organ toxicity, which, though eventually reversible, remains a serious concern.

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DOPC versus DOPE as a helper lipid for gene-therapies: molecular dynamics simulations with DLin-MC3-DMA

Abstract: A comparison of behavior of DOPC and DOPE lipids in the shell of lipid nano-particles.

Cited by 52 publications

References 89 publications

CHARMM-GUI Membrane Builder for Lipid Nanoparticles with Ionizable Cationic Lipids and PEGylated Lipids

CHARMM-GUI Membrane Builder for Lipid Nanoparticles with Ionizable Cationic Lipids and PEGylated Lipids

Nano Plasma Membrane Vesicle‐Lipid Nanoparticle Hybrids for Enhanced Gene Delivery and Expression

Impact of administration routes and dose frequency on the toxicology of SARS-CoV-2 mRNA vaccines in mice model

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