What are they?
Lipid nanoparticles (LNPs) are a crucial component in the delivery of RNA drugs, including mRNA-based therapeutics and small interfering RNA (siRNA) molecules. LNPs are utilized to protect and transport these fragile RNA molecules through the cell membrane to their target cells, ensuring efficient delivery and therapeutic effects.
How do they work?
In the case of RNA-based drugs, such as mRNA vaccines or therapeutics for genetic disorders, the RNA is encapsulated within a micelle of LNPs. These LNP micelles serve as protective carriers for the mRNA, shielding it from degradation by enzymes in the bloodstream.
First the drug, mRNA vaccines for example, is encapsulated within LNPs. For RNA interference (RNAi) drugs, such as small interfering RNA (siRNA) or short hairpin RNA (shRNA), the specific LNP’s used for the encapsulation may require a different LNPs with different properties to protect them during circulation and facilitate cell membrane transport. Lipids of several types, cholesterol, and short chain polyethylene glycol, have all been used in these encapsulation formulations. LNPs can also be modified with these specific ligands to enable targeted delivery to specific cell types or tissues. This is particularly useful when precision targeting is required.
LNPs interact with cell membranes and enter cells via endocytosis, a process where the cell engulfs the particle within a vesicle. This enables the efficient delivery of RNA molecules to the cytoplasm, where they can exert their therapeutic effects. After endocytosis, one of the critical challenges in RNA drug delivery is escaping from the endosome and reaching the cytoplasm where RNA molecules can function. LNPs facilitate endosomal escape through various mechanisms, including disruption of endosomal membranes so that the RNA can engage with the cellular machinery and carry out its therapeutic function. LNPs also help protect RNA molecules from degradation by ribonucleases, which ensures that enough intact RNA reaches the target cells.
Where have mRNA LNPs been used?
LNPs have extensively been used in the development of mRNA vaccines, such as the COVID-19 vaccines. They efficiently deliver the mRNA encoding the viral spike protein, triggering an immune response. LNPs have been created for use in gene therapy to deliver therapeutic mRNA molecules to treat genetic disorders, cancers, and other diseases. Additionally, they have been used in RNAi-based therapies, to deliver siRNA or other small RNA molecules to silence specific disease-related genes.
What are the advantages of mRNA delivery by LNPs over other methods?
LNPs are designed to be biocompatible and safe for clinical use, minimizing the risk of adverse effects sometimes observed in the use of viral vector RNA transporters. LNPs play a crucial role in maximizing the efficacy of RNA drugs by facilitating their efficient transport and intracellular release. Also, LNP properties are easier to be slightly modified or ‘tweaked’ to get a desired outcomes, than are viral vectors. This form of delivery is often the best option available for optimal drug efficacy.
What are the challenges of using LNPs as a mRNA transporter?
Researchers’ number one aim is to ensure the safety of a LNP RNA therapeutic formulation and to diminish any possible immunogenicity. Along with this, new encapsulation materials and novel designs must be optimized for efficacy of the therapeutic drug.
Summary
Lipid nanoparticles are vital vehicles for the delivery of RNA drugs, ensuring the protection, stability, and targeted delivery of RNA molecules to the appropriate cells, tissues, or organs in the body. This technology has opened a doorway for innovative therapies and vaccines in various areas of medicine. While challenges remain, ongoing research and advancements continue to enhance the potential of this approach for various biomedical applications for the treatment and prevention of a wide variety diseases. Potential applications range from vaccines to gene therapy to cancer treatments.
Reference
- Duan L-J, Wang Q, Zhang C, Yang D-X and Zhang X-Y (2022) “Potentialities and Challenges of mRNA Vaccine in Cancer Immunotherapy.” Front. Immunol. 47 (May 2022) 92366. Garcia-Beltran WF, et al. mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant. Cell. 2022;185:457–466
