Editorial Feature

RNA-Lipid Nanoparticles: A Hopeful Avenue in Gene Therapy

Lipid-based nanoparticles are a popular research area as a non-viral platform for delivering RNA molecules and include liposomes, lipoplexes, lipid nanoparticles and solid lipid nanoparticles. Using RNA-lipid nanoparticles and RNA delivery has become an exciting tool for developing advanced therapies for difficult-to-treat diseases such as neurological disorders.

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Lipid-based Nanoparticles

The biochemical composition of lipid-based nanoparticles provides many remarkable characteristics, including bio-mimicking and biodegradability, as well as the capacity to penetrate the blood-brain barrier (BBB) easier due to its lipophilicity. Additionally, these particles include cationic lipids that stabilize negatively charged RNA molecules through electrostatic interactions.

Lipid-based nanoparticles can include many different types, such as liposomes, which are self-assembled sphere-shaped vesicles with one or more phospholipid bilayers and can be used to deliver active molecules to target areas, with various formulations being used clinically.

Liposomes have been ubiquitously involved in drug delivery systems for treating a range of diseases, and there are currently more than 15 drugs involving liposomes on the market. However, encapsulating nucleic acids, such as RNA, is still an application that is undergoing development in pre-clinical or early clinical studies.

Lipid-based Nanoparticles in Gene Therapy

Developing liposomes for gene therapy involves using cationic lipids that interact electrostatically with negatively charged genetic material, with the most commonly used cationic lipids including DOTAP, DOTMA and DDA.

Recent research that has experimented with the use of liposomes with impact on the central nervous system included the development of DOTAP: Cholesterol 1:1 liposomes. These liposomes were incubated with small interfering RNA (siRNA) that reduced the amount of neuronal cellular prion proteins as well as rabies virus glycoprotein fragments.

The researchers’ formulations were found to effectively pass the BBB and increase the lifetime of prion-infected mice. Brain cells were targeted effectively through the use of the rabies virus glycoprotein fragments, while the therapeutic effect of the formulation allowed the siRNA to eliminate the expression of the prion proteins.

This research is significant as many neurodegenerative diseases are actually prion diseases, including but not limited to Alzheimer's, Parkinson’s and Huntington’s disease. The translation of this research for neurodegenerative disease treatment may be revolutionary, especially since these disorders lack effective treatments and cures.

Other research involving DOTAP:Cholesterol siRNA liposomes includes these particles being associated with transferrin, which was topically administered in mice brains and found significant evidence in the downregulation of pathological genes with low toxicity.

Interestingly, research into siRNA (siGOLPH3) loaded cationic liposomes that were combined with angiopep2GOLPH3 ligand for LRP-1 receptor, which is expressed in human BBB and glioma cells, was found to be promising for the potential treatment of glioma, a type of brain cancer.

Gliomas are the most common type of brain cancer, with approximately 33% of all brain tumors categorized as gliomas. Gliomas originate in the glial cells that surround neurons in the brain while also providing a supporting role. Glioblastomas are known as the most aggressive type of brain cancer and the use of RNA-lipid nanoparticles may hold the most potential for bypassing the BBB and effectively providing a novel therapeutic for these patient populations.

All About RNA

RNA is a significant payload for lipid nanoparticles and has been proven during the COVID-19 pandemic to hold great potential and efficacy through the development of vaccines. While RNA has been associated with being unstable in nature, research into ribonucleotides, nucleases and the molecular mechanism of inflammation has increased comprehension of its stability.

Exonucleases have been found, among other factors, to be involved in RNA instability, while 5’-capping and chemical modification of minimal nucleotides from both the 5’ and 3’ end, has been shown to be effective for increasing the stability of RNA.

RNA therapies can manipulate gene expression to generate therapeutic proteins, producing the development of drugs that are more suitable for diseases with well-established genetic targets.

Lipid nanoparticles can deliver genes into non-dividing cells, which can be useful for a range of diseases and disorders, for example, liver disease. Lipid nanoparticles have been shown to deliver a range of various genetic materials to the liver, including siRNA and mRNA encoding cDNA, Cas9 nuclease and related enzymes. The use of the CRISR/Cas9 system, which requires a guide RNA for genome editing, is also an interesting application for gene therapy for a range of diseases and disorders.

Future Outlook

The field of nanotechnology has been spearheading the advancement of medicine with novel innovations and developments being explored by researchers, and the use of RNA-lipid nanoparticles may be a revolutionary approach in gene therapy.

There are only a handful of approved cellular and gene therapy products that have been Food and Drug Administration (FDA) approved, and advancing this field through the use of RNA-lipid nanoparticles may hold significant potential, especially for diseases that require drugs that are too large to pass the BBB.

The use and development of RNA-lipid nanoparticles for gene therapy may be promising for a range of diseases, including neurodegenerative disorders that do not yet have a cure and allow for targeted treatment with minimal toxicity.

Solid Lipid Nanoparticles: An Overview

References and Further Reading

Akbarzadeh, A., et al. (2013). Liposome: classification, preparation, and applications. Nanoscale Research Letters, 8(1). doi.org/10.1186/1556-276x-8-102

Center for Biologics Evaluation and Research. Approved cellular and gene therapy products. U.S. Food and Drug Administration. Accessed November 8, 2023. Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products.

Gliomas. Johns Hopkins Medicine. February 11, (2022). Accessed November 8, 2023. Available at: https://www.hopkinsmedicine.org/health/conditions-and-diseases/gliomas.

Hou, X., et al. (2021). Lipid nanoparticles for mRNA delivery. Nature Reviews Materials, 6, pp.1078–1094. doi.org/10.1038/s41578-021-00358-0

Mashima, R. & Takada, S. (2022) Lipid nanoparticles: A novel gene delivery technique for clinical application. Current Issues in Molecular Biology, 44(10), pp. 5013-5027. doi.org/10.3390/cimb44100341

Paunovska, K., et al. (2022) Drug Delivery Systems for RNA therapeutics. Nature Reviews Genetics. 23(5), pp. 265-280. doi.org/10.1038/s41576-021-00439-4

Tsakiri, M., et al. (2022) Lipid-based nanoparticles and RNA as innovative neuro-therapeutics. Frontiers in Pharmacology. 13. doi.org/10.3389/fphar.2022.900610

Uddin, F., et al. (2020) CRISPR gene therapy: Applications, limitations, and implications for the future. Frontiers in Oncology, 10. doi.org/10.3389/fonc.2020.01387

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Marzia Khan

Written by

Marzia Khan

Marzia Khan is a lover of scientific research and innovation. She immerses herself in literature and novel therapeutics which she does through her position on the Royal Free Ethical Review Board. Marzia has a MSc in Nanotechnology and Regenerative Medicine as well as a BSc in Biomedical Sciences. She is currently working in the NHS and is engaging in a scientific innovation program.

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