Scientists have developed a new lipid nanoparticle that can safely deliver genetic codes into lung cells to treat various diseases.
Since the battle against COVID-19 began nearly two years ago, scientists have developed and released a range of drugs and medications, one of which is the RNA vaccine. Unlike conventional vaccines, which use inactivated or weakened versions of the virus, these RNA drugs are designed to carry genetic codes into our cells and prompt the production of viral proteins, thereby triggering our immune response. This method is significantly simpler compared to inserting or deleting DNAs as done in some gene therapies and has been shown to effectively tackle devastating diseases that are resistant to small molecule drugs or monoclonal antibodies. As such, experts believe that RNA drugs may hold the future of various treatments, or better yet, cures.
However, up until now, scientists are faced with major obstacles in safely delivering the genetic codes to targeted cells. One proven method, which has worked to target liver cells, is to encapsulate the RNA codes inside lipid nanoparticles that are covered with targeting ligands that can bind to specific cells. But this technique is complex as RNA drugs are unstable in vivo and have often failed to pass through cellular membranes when tested in clinical trials.
In light of these challenges, researchers from Japan’s Hokkaido University have assembled and tested a library of lipid-based compounds with the hope of finding a better “transporter” to safely and effectively deliver RNA drugs to different organs. Their study has led them to identify a promising lipid polymer that may be useful in treating acute respiratory distress syndrome, pulmonary hypertension, and lung cancers.
Led by pharmaceutical scientist Hideyoshi Harashima and polymer chemist Toshifumi Satoh, the team developed a library of ε-decalactone-based compounds, which are lipids that could bypass the liver and specifically deliver RNA code into the lungs. They then selected two closely related ring-shaped compounds, ε-caprolactone and ε-decalactone, for further investigation. Because previous studies have shown that lipid nanoparticles containing these lactones accumulated in the lungs, the scientists subjected the lipids to ring-opening reactions using one of eleven amino alcohols.
Afterwards, the scientists further classified the resulting products based on the molecular weight of each arm. The products were then combined with mRNA and DMG-PEG, which is a synthetic lipid formed by the PEGylation of myristoyl diglyceride and an important component in manufacturing lipid nanoparticles. Together, the lipid, mRNA, and DMG-PEG form the new mRNA-carrying nanoparticle.
When the nanoparticles made with the two different lipids were compared, it was observed that nanoparticles from ε-caprolactone were more unstable than ones made with ε-decalactone. As such, the team proceeded with their experiments with only ε-decalactone-based nanoparticles.
To determine the efficacy of their newly developed lipid carrier, Harashima, Satoh, and colleagues tried testing the RNA-carrying ε-decalactone nanoparticles on laboratory cancer cells before proceeding with mice models. Using mRNA encoding enhanced green fluorescence protein, they were able to track the route and identify the destination of the nanoparticles upon administration.
Their findings revealed that combining ε-decalactone with a linear amino alcohol called AA03 resulted in the best outcome. The nanoparticles containing this polymer were found to largely bypass the liver and carry the RNA material specifically into the lungs. They also observed that the nanoparticles could be engulfed by the cell membrane, after which the contents of the RNA were released into the cytoplasm of the lung cells and translated.
We showed that expanding the chemical space of smart materials could enable the fabrication of nanoparticles for hard-to-reach targets without the need for targeting ligands,” explained Harashima.
Having demonstrated the potential of their new lipid transporter, it is hoped that this innovation can improve the delivery of RNA drugs and eventually be modified to carry therapeutics not only to the liver and lungs, but many other organs. As said by Harashima, “Designing combinatorial libraries that provide diverse ε-decalactone lipomers could be an easy and scalable strategy for the development of next-generation gene therapies for organs beyond the liver.” [APBN]
Source: Elwakil et al. (2021). Engineered ε-decalactone lipomers bypass the liver to selectively in vivo deliver mRNA to the lungs without targeting ligands. Materials Horizons.