Development of a Library of Disulfide Bond-Containing Cationic Lipids for mRNA Delivery

Shen, ZG; Liu, C; Wang, ZQ; Xie, FF; Liu, XW; Dong, LK; Pan, XH; Zeng, C; Wang, PG

Abstract

Lipid nanoparticles (LNPs) are the commonly used delivery tools for messenger RNA (mRNA) therapy and play an indispensable role in the success of COVID-19 mRNA vaccines. Ionizable cationic lipids are the most important component in LNPs. Herein, we developed a series of new ionizable lipids featuring bioreducible disulfide bonds, and constructed a library of lipids derived from dimercaprol. LNPs prepared from these ionizable lipids could be stored at 4 degrees C for a long term and are non-toxic toward HepG2 and 293T cells. In vivo experiments demonstrated that the best C4S18A formulations, which embody linoleoyl tails, show strong firefly luciferase (Fluc) mRNA expression in the liver and spleen via intravenous (IV) injection, or at the local injection site via intramuscular injection (IM). The newly designed ionizable lipids can be potentially safe and high-efficiency nanomaterials for mRNA therapy.

Keywords: lipid nanoparticles; mRNA delivery; disulfide bond

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Liposomes for DNA/RNA Delivery

The development of a cationic lipid library represents a significant advancement in the field of mRNA delivery. Cationic lipids, with their positive charge, efficiently form complexes with negatively charged mRNA, facilitating cellular uptake and protecting the mRNA from degradation. By systematically varying the lipid structures, researchers can identify optimal formulations that enhance delivery efficiency, stability, and transfection efficacy. This approach allows for the fine-tuning of lipid characteristics such as head group charge, hydrophobic tail length, and the inclusion of helper lipids, which collectively improve the biophysical properties and performance of the lipid nanoparticles (LNPs). Effective mRNA delivery systems are crucial for a range of applications, including vaccines, gene therapy, and protein replacement therapies. The cationic lipid library approach accelerates the discovery of new lipid formulations that maximize mRNA expression in target cells, offering a versatile and powerful platform for advancing mRNA-based therapeutics.