Design of NOF’s Ionizable Lipids Achieving Low Toxicity and Reduced Immunogenicity for Non-Viral RNA Therapeutics

Since the COVID‑19 pandemic, there has been growing interest in using ionizable lipids for gene delivery in gene editing and enzyme replacement therapy. However, many of the ionizable lipids currently available were originally developed for vaccines and were selected based on immunogenicity-related properties. Consequently, repurposing vaccine-derived LNPs for repeated systemic dosing in mRNA therapeutics is challenging because cumulative exposure can produce dose-limiting toxicities. In this study, we report the rational design and characterization of biodegradable ionizable lipids that provide improved tolerability, while maintaining robust in vivo mRNA expression. We further provide metabolism and excretion data to support their favorable safety and clearance profiles. This presentation will cover hepatic gene delivery using LNPs formulated with NOF’s proprietary ionizable lipids, spleen‑targeted delivery by formulation optimization, and potential applications for infectious disease vaccines and repeated‑dose mRNA therapeutics. (134 words)