Muthusamy et al. synthesized DLin-MC3-DMA with good delivery efficiency and safety in 2012. The head linker of Dlin-MC3-DMA replaced the ether bond with an ester bond, making Dlin-MC3-DMA degradable in vivo. The invention of Dlin-MC3-DMA is considered a milestone event in the development history of ionizable lipid molecules.

DLin-MC3-DMA exhibits unique pH dependent charge variability: it is positively charged under acidic conditions and electrically neutral under physiological pH conditions. Its successful application in Onpattro has become the key to Alnylam's siRNA delivery technology and is the "standard" lipid material for preparing liver targeted siRNA/LNP systems.

RNAi (RNA interference), as a sequence specific gene silencing technique, has attracted significant attention in the field of gene therapy for malignant tumors. Among them, siRNA (small interfering RNA) is an effector molecule in the RNAi pathway, which can specifically degrade homologous sequences of mRNA, express specific genes, and achieve the goals of growth, invasion, and metastasis. It is currently one of the important hotspots in the forefront research of new drug development. Due to the polyanionic center and strong hydrophilic groups of siRNA itself, it cannot enter the cytoplasm through passive transport. In addition, siRNA is easily degraded by nucleases in the cytoplasm, making exogenous siRNA unable to directly enter the cytoplasm to exert its efficacy. Therefore, finding suitable transport carriers is the primary issue for siRNA * *.

Lipid nanoparticles (LNPs) have been proven to be effective as delivery systems for traditional small molecule drugs. Liposomes are non-toxic, non immunogenic, naturally degradable, biocompatible, and easily surface modified non viral carriers. Research has found that ionizable cationic liposome nanoparticles can encapsulate siRNA with polyanion centers through electrostatic interactions to form LNPs/siRNA complexes. These complexes can effectively protect siRNA from degradation by nucleases during internalization by target cells, allowing it to enter the cytoplasm smoothly. Then, LNPs/siRNA complexes separate and the corresponding siRNA exerts its efficacy. Zimmermann et al. used the LNPs system to transport anti apoB siRNA, and the results showed that it could effectively reduce the levels of apoB protein, low-density lipoprotein, and cholesterol in monkey liver. Among numerous ionizable cationic liposomes, DLin-MC3-DMA is considered one of the widely used cationic liposomes.