Developing sulfonium lipid nanoparticles as a novel platform for mRNA delivery - SUMMARY Lipid nanoparticles (LNPs) are the most clinically advanced system for mRNA delivery, as highlighted by the FDA approvals of Spikevax® and Comirnaty®. However, there is no one-fit-all lipid design; lipids that perform well for one application may not work effectively across different cell types or medical conditions. This underscores the need to expand the lipid molecular toolbox to address evolving therapeutic challenges. By introducing sulfonium as a charge-carrying unit to replace traditional amines, we first demonstrated the safety and feasibility of using unconventional, non-amine-based sulfonium lipids for mRNA delivery. Building on these promising results, we propose to further develop sulfonium lipid nanoparticles (sLNPs) as a new platform for mRNA delivery. We will expand the chemical diversity of sulfonium lipids by incorporating novel building blocks, laying the groundwork for structure-activity relationship studies. Similar to amine-based lipids, variations in the head, linker, and tail structures of sulfonium lipids will likely affect self-assembly, cargo delivery, and biocompatibility. A detailed mechanistic investigation will uncover the unique physicochemical and biological properties of sLNPs. Additionally, we will explore the therapeutic potential of organ-targeting mRNA/sLNP formulations for treating acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in clinically relevant small animal models, providing robust preclinical evidence to pave the way for future translational research of sLNP technology.
