Nucleic acid therapeutics are a growing sector of pharmacy, encompassing a wide range of applications from vaccines to gene editing. Among the available delivery systems for RNA therapies, lipid nanoparticles (LNPs) are a popular choice, rising to prominence for their use in the Moderna and Pfizer-BioNTech COVID-19 vaccines. However, the toxicity of ionisable lipids limits their clinical use.
This led NOF Corporation to pursue a molecular design to limit the toxicity of the delivery system to reach the full potential of nucleic acid therapies. This presentation outlines NOF Corporation’s COATSOME SS Series: a biodegradable lipid nanoparticle technology for gene therapy and vaccine delivery.
LNPs are typically composed of four lipids: ionisable lipid, cholesterol, helper lipid, and PEG lipid, with the ionisable lipid being crucial for efficacy and cytotoxicity. What sets NOF’s SS-Series apart is its novel ionisable lipid which can be easily degraded in cytoplasmic conditions. They have developed two novel SS lipids: SS-EC with applications for cancer vaccines and SS-OP for hepatic and splenic delivery, infectious disease vaccines, and ex vivo transfection.
SS-lipids get their name from the disulphide bond in the head group. This bond can be cleaved in the reductive environment of the cytoplasm. Furthermore, the lipid’s tertiary amines respond to an acidic compartment of the endosome or lysosome for membrane destabilisation. Finaly, SS-Series also contains dual sensing motifs that can respond to the intracellular environment.
The LNP is not charged under physiological conditions, but once taken up into the cell via endocytosis, it becomes positively charged under acidic conditions. Then the LNP interacts with the negatively charged endosomal membrane which leads to membrane fusion and release of the core into the cytosol. There, the high concentration of glutathione rapidly reduces the disulfide bonds of the SS lipids, releasing the nucleic acid cargo.
SS-OP lipids demonstrate lower systemic toxicity and higher gene expression activity compared to competitor lipids, indicating its potential for safe and effective RNA delivery. Furthermore, SS lipids can be used in hepatic delivery, splenic delivery, and RNA vaccine formulations, indicating their versatility in targeting specific organs. SS-EC lipid is particularly noted for its adjuvant properties, making it suitable for cancer vaccine applications, while SS-OP is effective for RNA delivery.
The presentation also showed data on the immunogenic response elicited by SS-OP and SS-EC, demonstrating enhanced IgG production and CTL activity, which are critical for effective vaccines. The SS lipids show promising long-term storage stability and can be modified for active targeting, enhancing their delivery efficiency in vivo.
