Ionizable Lipid

Ionizable lipids are lipid compounds containing ionizable functional groups (such as amines, carboxylates or guanidine groups). Ionizable functional groups can be protonated or deprotonated according to the pH value of the surrounding environment, resulting in changes in the overall charge and hydrophobicity of lipids. This pH-dependent behavior is a key feature of ionizable lipids and is critical to their function in drug delivery systems. For example, ionizable lipids can form stable complexes with negatively charged molecules (such as mRNA) through electrostatic interactions, thereby promoting cytoplasmic transport. Due to their unique properties and potential applications, ionizable lipids have received great attention in the field of drug delivery and gene therapy.

BOC Sciences offers a variety of ionizable lipid products to support research applications in pharmaceutical, biotechnology and drug delivery. We have a comprehensive portfolio of ionizable lipid products, including: DODAP derivatives, DODAC derivatives, DOPE derivatives, DSPE-PEG, etc. We also offer custom synthesis of lipids and one-stop analysis services. If you are interested in our lipid products or services, please contact us for more information.

Structure of Ionizable Lipids

The structure of ionizable lipids is generally divided into three parts: a hydrophilic head group containing an ionizable amino group, a connecting bond, and a hydrophobic tail chain.

Ionizable lipid nanoparticles for mRNA deliveryFig. 1. Ionizable lipid nanoparticles for mRNA delivery (Bioactive Materials. 2024, 34: 125-137).

Ionizable Head Group

The type of head group will affect the apparent acid dissociation constant (pKa), particle size and endosomal escape efficiency of ionizable lipids. Jayaraman et al. adjusted the pKa of ionizable lipids through systematic structural screening of hydrophilic head groups and studied the relationship between pKa value and activity. Different head groups were designed including primary amines, secondary amines, tertiary amines, quaternary ammonium and pyridinium salts. It was found that changes in headgroup structure affect the size of the hydrophilic region.


In lipid structures, common connections between hydrophilic head groups and hydrophobic tail chains include ester bonds, ether bonds, carbamates, thioether bonds, hydrazine, hydroxylamine, ethanolamine, and amides. The type of linker also has an important impact on delivery efficiency. For example, Semple et al. synthesized DLin-DAP, DLin-DMA, DLin-C-DAP and DLin-S-DMA with the same head group tail chain and ester bond, ether bond, carbamate bond and thioether bond, respectively, to study the effect of connection bond on transfection efficiency. Lipid nanoparticles (LNP) (~71nm) prepared by DLin-DMA with ether bond had the highest efficiency of silencing coagulation factor VII in mouse model, and the ED50 value was 1mg·kg-1. The LNP (~ 65nm) prepared by DLin-DAP with the ester bond as the connecting bond had the worst gene silencing efficiency in vivo, and the ED50 value was only 45mg·kg-1.

Hydrophobic Tail

The length and degree of unsaturation of the hydrophobic tail chain can affect lipophilicity, fluidity, fusibility, pKa, etc., thereby affecting the effectiveness of ionizable lipids. Alkane chains with 8 to 18 carbon atoms, cholesterol derivatives or tocopherol derivatives with different degrees of saturation can be used as the hydrophobic part of the lipid. Heyes et al. studied the relationship between lipid saturation, fluidity and intracellular nucleic acid delivery efficiency, and constructed four ionizable lipids containing DSDMA, DODMA, DLinDMA and DLenDMA containing tertiary amine head groups and tail chains with different saturations. This series of lipids successfully delivered Luciferase siRNA to mouse brain neuroma (Neuro2A) cells in vitro.

Ionizable Lipids in Drug Delivery

Ionizable lipids are promising components in drug delivery systems because they can encapsulate therapeutic agents and deliver them to target cells or tissues. The pH-dependent charge characteristics of ionizable lipids enable them to undergo structural changes in response to changes in local pH environments (such as acidic endosomal compartments of cells). This pH-responsive behavior enables ionizable lipids to promote intracellular release of encapsulated drugs, thereby enhancing their therapeutic efficacy. In addition, ionizable lipids can interact with negatively charged biofilms through electrostatic interactions to promote cellular uptake and endosomal escape of encapsulated goods. The ability of ionizable lipids to disrupt endosomal membrane stability and release their cargo into the cytoplasm is a key advantage in improving the delivery of nucleic acids, proteins, and small molecules to target cells.

Ionizable Lipids in Gene Therapy

In the field of gene therapy, ionizable lipids have shown great potential in delivering nucleic acids (such as plasmid DNA, messenger RNA, and small interfering RNA) to target cells for gene expression regulation or gene silencing. The cationic properties of ionizable lipids enable them to form complexes with negatively charged nucleic acids through electrostatic interactions, thereby protecting nucleic acids from degradation and promoting their cellular uptake. In addition, the pH-dependent behavior of ionizable lipids allows them to escape from the endosome after cellular uptake, promoting the release of nucleic acids into the cytoplasm, where they can play a therapeutic role. This endosomal escape mechanism is essential for improving the transfection efficiency of gene delivery systems and reducing the cytotoxicity associated with non-viral gene delivery vectors.

Case Study

Case Study 1

Ramishetti et al. constructed a lipid library based on ionizable lipid DLin-MC3-DMA, which contains hydrazine, hydroxylamine and ethanolamine. The prepared lipid nanoparticles (LNP) have a particle size of about 100nm. Integrin β7 antibody was modified to the surface of LNP loaded with CD45 siRNA for targeting CD4+ and CD8+ T-lymphocytes in vivo. The results showed that when the dose of 1mg·kg-1 was injected into the tail vein of mice, LNPs containing hydrazine-linked lipids had almost no silencing effect, while LNPs containing hydroxylamine-linked lipids and ethanolamine-linked lipids showed better performance in T-lymphocytes. It has a significant gene silencing effect, with a silencing efficiency of approximately 40%. This research provides a new method for effectively delivering siRNA to specific cells in the body.

Case Study 2

Akinc et al. constructed a series of ionizable lipid libraries with amide bonds and ester bonds as the connecting bonds. In the case of the same head group and tail chain, the effect of the change of the connecting bond on the silencing effect of LNP was investigated. The results of in vitro screening experiments showed that in human cervical cancer (HeLa) cells, 2 of the LNP constructed with ester bond as the connecting bond lipid had an in vitro silencing efficiency better than 60%, while 12 of the LNP prepared with amide bond as the connecting bond lipid had an in vitro silencing efficiency better than 60%. In the mouse model, at the dose of 2.5mg·kg-1 siRNA injected for two consecutive days, the lipid 98N12 LNP containing the amide linkage had the strongest gene silencing efficiency in vivo, and the silencing efficiency of coagulation factor VII reached 95%.


  1. Riley, R.S. et al. Systematic development of ionizable lipid nanoparticles for placental mRNA delivery using a design of experiments approach. Bioactive Materials. 2024, 34: 125-137.

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