In this study, he synthesis of amidine-incorporated degradable (AID) lipids for mRNA delivery involves a novel and efficient method utilizing a one-pot, tandem multi-component reaction. This method employs amine, thiol, and acrylate components and is conducted at room temperature, allowing for the fast synthesis of AID lipids within just one hour. The amidine incorporation is a rational design choice aimed at ensuring the degradability of the lipids. A library of 100 chemically diverse AID lipids was synthesized and analyzed to establish structure–activity relationships.
From this analysis, a tail-like amine–ring-alkyl aniline structure emerged as particularly efficacious. The embedded bulky benzene ring within this structure facilitates the lipid adopting a more conical shape, which enhances endosomal escape and improves mRNA delivery. Experimental and theoretical studies confirmed that this structural feature is beneficial for these processes.
The synthesized AID lipids demonstrated significant functional capabilities. They effectively mediate both local delivery of mRNA vaccines and systemic delivery of mRNA therapeutics. Additionally, these lipids can alter the tropism of liver-tropic lipid nanoparticles (LNPs), allowing them to selectively deliver gene editors to the lungs and mRNA vaccines to the spleen. This method significantly simplifies the synthesis process, enabling the rapid generation and testing of new lipid candidates, facilitating scalable manufacturing, and supporting versatile applications in mRNA delivery.
