Soybean Oil-Derived Lipids for Efficient mRNA Delivery

Lipids have been extensively utilized as a delivery platform for mRNA. Lipids consist of an N element-based head group with hydrophobic tails of varying composition and different length. Currently, most lipid materials are either positively charged or ionizable in nature, which allows for the formation of nanoparticles through electrostatic interactions with negatively charged mRNA. This not only serves to safeguard mRNA from enzymatic degradation but also facilitates endosomal escape, thereby ensuring mRNA expression and functions. In addition to core lipids, the delivery platform comprises helper lipids, cholesterol, and PEG lipids. Varying compositions, surface modifications, charges, and pKa values can impact mRNA expression and allow organ-specific targeting for disease treatment. Hence, continued investigation of novel lipid materials and formulations will further advance our understanding and techniques in optimizing mRNA delivery.<br/><br/>The ideal synthesis of lipids involves adhering to key principles, such as operating under solvent-free conditions, employing a straightforward reaction process, and eliminating the need for purification steps. These criteria aim to enhance product purity and streamline production, thereby increasing the likelihood for clinical translation. Current lipid synthesis methods involve Michael addition, epoxide ring-opening, reductive amination, and thiol-ene reactions. Furthermore, an effective lipid should encapsulate a high mRNA payload for improved expression <i>in vivo</i> and exhibit favorable biosafety without significant adverse effects. Notably, a common soybean oil derivative, rich in epoxy groups, can readily undergo ring-opening reactions with amino-containing compounds. Since soybean oil is FDA-approved and has excellent biocompatibility, it may give rise to a new class of synthetic lipid materials with the potential for mRNA delivery applications.<br/><br/>In our system, epoxidized soybean oil and amino-containing compounds with varying carbon chain lengths, structures, and numbers of N were the sole reactants. Lipids were synthesized via epoxide ring-opening reactions and subsequently purified through heating and rotary evaporation, all without the use of solvents. We found that the majority of lipids derived from soybean oil showed high mRNA loading capacity, thereby enhancing mRNA expression both in vitro and in vivo, all the while demonstrating excellent biosafety. In our <i>in vivo</i> studies of Luc mRNA delivery, we observed that certain lipids could enhance mRNA expression in the spleen, while others could achieve high expression in the lungs or liver. This highlights the potential utility of these lipids for precise and tunable organ targeting in the treatment of relevant diseases. In addition, soybean oil-derived lipids displayed exceptional performance in delivering Cre mRNA for gene editing. Encouraged by these results, we anticipate that soybean oil-derived lipid materials can assume a more prominent role in the realm of mRNA delivery for a diverse range of bioapplications. The synthesis of novel lipids utilizing FDA-approved substances remains a promising domain yet to be fully explored.