Browse
Submit Data
Databases
API
Help

Dataset Information

25 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Tuning the Immunostimulation Properties of Cationic Lipid Nanocarriers for Nucleic Acid Delivery.

ABSTRACT: Nonviral systems, such as lipid nanoparticles, have emerged as reliable methods to enable nucleic acid intracellular delivery. The use of cationic lipids in various formulations of lipid nanoparticles enables the formation of complexes with nucleic acid cargo and facilitates their uptake by target cells. However, due to their small size and highly charged nature, these nanocarrier systems can interact in vivo with antigen-presenting cells (APCs), such as dendritic cells (DCs) and macrophages. As this might prove to be a safety concern for developing therapies based on lipid nanocarriers, we sought to understand how they could affect the physiology of APCs. In the present study, we investigate the cellular and metabolic response of primary macrophages or DCs exposed to the neutral or cationic variant of the same lipid nanoparticle formulation. We demonstrate that macrophages are the cells affected most significantly and that the cationic nanocarrier has a substantial impact on their physiology, depending on the positive surface charge. Our study provides a first model explaining the impact of charged lipid materials on immune cells and demonstrates that the primary adverse effects observed can be prevented by fine-tuning the load of nucleic acid cargo. Finally, we bring rationale to calibrate the nucleic acid load of cationic lipid nanocarriers depending on whether immunostimulation is desirable with the intended therapeutic application, for instance, gene delivery or messenger RNA vaccines.

SUBMITTER: Dey AK

PROVIDER: S-EPMC8419413 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Cholesterol Sequestration from Caveolae/Lipid Rafts Enhances Cationic Liposome-Mediated Nucleic Acid Delivery into Endothelial Cells.

Project description:Delivering nucleic acids into the endothelium has great potential in treating vascular diseases. However, endothelial cells, which line the vasculature, are considered as sensitive in nature and hard to transfect. Low transfection efficacies in endothelial cells limit their potential therapeutic applications. Towards improving the transfection efficiency, we made an effort to understand the internalization of lipoplexes into the cells, which is the first and most critical step in nucleic acid transfections. In this study, we demonstrated that the transient modulation of caveolae/lipid rafts mediated endocytosis with the cholesterol-sequestrating agents, nystatin, filipin III, and siRNA against Cav-1, which significantly increased the transfection properties of cationic lipid-(2-hydroxy-N-methyl-N,N-bis(2-tetradecanamidoethyl)ethanaminium chloride), namely, amide liposomes in combination with 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) (AD Liposomes) in liver sinusoidal endothelial cells (SK-Hep1). In particular, nystatin was found to be highly effective with 2-3-fold enhanced transfection efficacy when compared with amide liposomes in combination with Cholesterol (AC), by switching lipoplex internalization predominantly through clathrin-mediated endocytosis and macropinocytosis.

| S-EPMC8346983 | biostudies-literature

Cationic liposome-nucleic acid complexes for gene delivery and gene silencing.

Project description:Cationic liposomes (CLs) are studied worldwide as carriers of DNA and short interfering RNA (siRNA) for gene delivery and gene silencing, and related clinical trials are ongoing. Optimization of transfection efficiency and silencing efficiency by cationic liposome carriers requires a comprehensive understanding of the structures of CL-nucleic acid complexes and the nature of their interactions with cell membranes as well as events leading to release of active nucleic acids within the cytoplasm. Synchrotron x-ray scattering has revealed that CL-nucleic acid complexes spontaneously assemble into distinct liquid crystalline phases including the lamellar, inverse hexagonal, hexagonal, and gyroid cubic phases, and fluorescence microscopy has revealed CL-DNA pathways and interactions with cells. The combining of custom synthesis with characterization techniques and gene expression and silencing assays has begun to unveil structure-function relations in vitro. As a recent example, this review will briefly describe experiments with surface-functionalized PEGylated CL-DNA nanoparticles. The functionalization, which is achieved through custom synthesis, is intended to address and overcome cell targeting and endosomal escape barriers to nucleic acid delivery faced by PEGylated nanoparticles designed for in vivo applications.

| S-EPMC4288823 | biostudies-literature

A cationic amphiphilic co-polymer as a carrier of nucleic acid nanoparticles (Nanps) for controlled gene silencing, immunostimulation, and biodistribution.

Project description:Programmable nucleic acid nanoparticles (NANPs) provide controlled coordination of therapeutic nucleic acids (TNAs) and other biological functionalities. Beyond multivalence, recent reports demonstrate that NANP technology can also elicit a specific immune response, adding another layer of customizability to this innovative approach. While the delivery of nucleic acids remains a challenge, new carriers are introduced and tested continuously. Polymeric platforms have proven to be efficient in shielding nucleic acid cargos from nuclease degradation while promoting their delivery and intracellular release. Here, we venture beyond the delivery of conventional TNAs and combine the stable cationic poly-(lactide-co-glycolide)-graft-polyethylenimine with functionalized NANPs. Furthermore, we compare several representative NANPs to assess how their overall structures influence their delivery with the same carrier. An extensive study of various formulations both in vitro and in vivo reveals differences in their immunostimulatory activity, gene silencing efficiency, and biodistribution, with fibrous NANPs advancing for TNA delivery.

| S-EPMC6942546 | biostudies-literature

Dendrimers as Nanocarriers for Nucleic Acid and Drug Delivery in Cancer Therapy.

Project description:Dendrimers are highly branched polymers with easily modifiable surfaces. This makes them promising structures for functionalization and also for conjugation with drugs and DNA/RNA. Their architecture, which can be controlled by different synthesis processes, allows the control of characteristics such as shape, size, charge, and solubility. Dendrimers have the ability to increase the solubility and bioavailability of hydrophobic drugs. The drugs can be entrapped in the intramolecular cavity of the dendrimers or conjugated to their functional groups at their surface. Nucleic acids usually form complexes with the positively charged surface of most cationic dendrimers and this approach has been extensively employed. The presence of functional groups in the dendrimer's exterior also permits the addition of other moieties that can actively target certain diseases and improve delivery, for instance, with folate and antibodies, now widely used as tumor targeting strategies. Dendrimers have been investigated extensively in the medical field, and cancer treatment is one of the greatest areas where they have been most used. This review will consider the main types of dendrimer currently being explored and how they can be utilized as drug and gene carriers and functionalized to improve the delivery of cancer therapy.

| S-EPMC5600151 | biostudies-other

Lipid Nanoparticles for Nucleic Acid Delivery to Endothelial Cells.

Project description:Endothelial cells play critical roles in circulatory homeostasis and are also the gateway to the major organs of the body. Dysfunction, injury, and gene expression profiles of these cells can cause, or are caused by, prevalent chronic diseases such as diabetes, cardiovascular disease, and cancer. Modulation of gene expression within endothelial cells could therefore be therapeutically strategic in treating longstanding disease challenges. Lipid nanoparticles (LNP) have emerged as potent, scalable, and tunable carrier systems for delivering nucleic acids, making them attractive vehicles for gene delivery to endothelial cells. Here, we discuss the functions of endothelial cells and highlight some receptors that are upregulated during health and disease. Examples and applications of DNA, mRNA, circRNA, saRNA, siRNA, shRNA, miRNA, and ASO delivery to endothelial cells and their targets are reviewed, as well as LNP composition and morphology, formulation strategies, target proteins, and biomechanical factors that modulate endothelial cell targeting. Finally, we discuss FDA-approved LNPs as well as LNPs that have been tested in clinical trials and their challenges, and provide some perspectives as to how to surmount those challenges.

| S-EPMC9897626 | biostudies-literature

Development of Theranostic Cationic Liposomes Designed for Image-Guided Delivery of Nucleic Acid.

Project description:Cationic liposomes have been considered as potential vectors for gene delivery thanks to their ability to transfect cells with high efficiency. Recently, the combination of diagnostic agent and therapeutic agents in the same particle to form a theranostic system has been reported. Magnetic liposomes are one of these examples. Due to the magnetic nanoparticles encapsulated in the liposomes, they can act as a drug delivery system and, at the same time, a magnetic resonance imaging contrast enhancement agent or hyperthermia. In this work, nucleic acid delivery systems based on magnetic cationic liposomes (MCLs) were developed. Two different techniques, reverse phase evaporation and cosolvent sonication, were employed for liposome preparation. Both strategies produced MCLs of less than 200 nm with highly positive charge. Enhancement of their transverse and longitudinal relaxivities r2and r1 was obtained with both kinds of magnetic liposomes compared to free magnetic nanoparticles. Moreover, these MCLs showed high capacity to form complexes and transfect CT-26 cells using the antibiotic-free pFAR4-luc plasmid. The transfection enhancement with magnetofection was also carried out in CT26 cells. These results suggested that our MCLs could be a promising candidate for image-guided gene therapy.

| S-EPMC7559777 | biostudies-literature

Lipid-Based Nanocarriers for RNA Delivery.

Project description:RNA-interference (RNAi) agents such as small-interfering RNA (siRNA) and micro-RNA (miRNA) have strong potential as therapeutic agents for the treatment of a broad range of diseases such as malignancies, infections, autoimmune diseases and neurological diseases that are associated with undesirable gene expression. In recent years, several clinical trials of RNAi therapeutics especially siRNAs have been conducted with limited success so far. For systemic administration of these poorly permeable and easily degradable macromolecules, it is obvious that a safe and efficient delivery platform is highly desirable. Because of high biocompatibility, biodegradability and solid track record for clinical use, nanocarriers made of lipids and/or phospholipids have been commonly employed to facilitate RNA delivery. In this article, the key features of the major sub-classes of lipid-based nanocarriers, e.g. liposomes, lipid nanoparticles and lipid nanoemulsions, will be reviewed. Focus of the discussion is on the various challenges researchers face when developing lipid-based RNA nanocarriers, such as the toxicity of cationic lipids and issues related to PEGylated lipids, as well as the strategies employed in tackling these challenges. It is hoped that by understanding more about the pros and cons of these most frequently used RNA delivery systems, the pharmaceutical scientists, biomedical researchers and clinicians will be more successful in overcoming some of the obstacles that currently limit the clinical translation of RNAi therapy.

| S-EPMC4618487 | biostudies-literature

Nucleic acid-mediated intracellular protein delivery by lipid-like nanoparticles.

Project description:Intracellular protein delivery has potential biotechnological and therapeutic application, but remains technically challenging. In contrast, a plethora of nucleic acid carriers have been developed, with lipid-based nanoparticles (LNPs) among the most clinically advanced reagents for oligonucleotide delivery. Here, we validate the hypothesis that oligonucleotides can serve as packaging materials to facilitate protein entrapment within and intracellular delivery by LNPs. Using two distinct model proteins, horseradish peroxidase and NeutrAvidin, we demonstrate that LNPs can yield efficient intracellular protein delivery in vitro when one or more oligonucleotides have been conjugated to the protein cargo. Moreover, in experiments with NeutrAvidin in vivo, we show that oligonucleotide conjugation significantly enhances LNP-mediated protein uptake within various spleen cell populations, suggesting that this approach may be particularly suitable for improved delivery of protein-based vaccines to antigen-presenting cells.

| S-EPMC5259800 | biostudies-literature

Influence of cationic lipid concentration on properties of lipid-polymer hybrid nanospheres for gene delivery.

Project description:Nanoparticles have been widely used for nonviral gene delivery. Recently, cationic hybrid nanoparticles consisting of two different materials were suggested as a promising delivery vehicle. In this study, nanospheres with a poly(D,L-lactic-co-glycolic acid) (PLGA) core and cationic lipid shell were prepared, and the effect of cationic lipid concentrations on the properties of lipid polymer hybrid nanocarriers investigated. Lipid-polymer hybrid nanospheres (LPHNSs) were fabricated by the emulsion-solvent evaporation method using different concentrations of cationic lipids and characterized for size, surface charge, stability, plasmid DNA-binding capacity, cytotoxicity, and transfection efficiency. All LPHNSs had narrow size distribution with positive surface charges (ζ-potential 52-60 mV), and showed excellent plasmid DNA-binding capacity. In vitro cytotoxicity measurements with HEK293T, HeLa, HaCaT, and HepG2 cells also showed that LPHNSs exhibited less cytotoxicity than conventional transfection agents, such as Lipofectamine and polyethyleneimine-PLGA. As cationic lipid concentrations increased, the particle size of LPHNSs decreased while their ζ-potential increased. In addition, the in vitro transfection efficiency of LPHNSs increased as lipid concentration increased.

| S-EPMC4567174 | biostudies-literature

The Future of Tissue-Targeted Lipid Nanoparticle-Mediated Nucleic Acid Delivery.

Project description:The earliest example of in vivo expression of exogenous mRNA is by direct intramuscular injection in mice without the aid of a delivery vehicle. The current state of the art for therapeutic nucleic acid delivery is lipid nanoparticles (LNP), which are composed of cholesterol, a helper lipid, a PEGylated lipid and an ionizable amine-containing lipid. The liver is the primary organ of LNP accumulation following intravenous administration and is also observed to varying degrees following intramuscular and subcutaneous routes. Delivery of nucleic acid to hepatocytes by LNP has therapeutic potential, but there are many disease indications that would benefit from non-hepatic LNP tissue and cell population targeting, such as cancer, and neurological, cardiovascular and infectious diseases. This review will concentrate on the current efforts to develop the next generation of tissue-targeted LNP constructs for therapeutic nucleic acids.

| S-EPMC9322927 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data