Following the success of mRNA vaccines against COVID-19, few topics in biomedical research have attracted as much attention as nucleic acid therapeutics. The therapeutic potential of these biomolecules extends far beyond preventive vaccines: Nucleic acid-based therapeutics hold promise for the treatment of a wide range of diseases, including infectious and genetic disorders as well as cancer [1]. However, the success of these innovative therapies depends critically on whether and how the therapeutic agent reaches its target within the body – in other words, delivery. After all, even the most promising therapeutic can only exert its effects if it reaches the place where it is needed. RNA, in particular, presents a challenge: It is highly unstable, rapidly degraded by enzymes in the body, and cannot readily cross the cell membrane [2]. The right packaging is therefore crucial. And sometimes, a little fat can go a long way: The breakthrough for mRNA-based COVID-19 vaccines came with the development of so-called lipid nanoparticles (LNPs).
If you are picturing simple little balls of fat, think again. LNPs are far more complex structures composed of multiple components. The precise composition of the different lipids is crucial, as it influences properties such as stability and pharmacokinetics [3]. Together, the lipids form a protective shell around the sensitive mRNA molecules, enabling their efficient delivery into cells [2]. Our partner Cayman Chemical offers an extensive selection of lipids for customized LNP formulation. This allows you to tailor the composition of your LNPs to the specific application and biomolecule you want to deliver.
1) mRNA Vaccines in Abundance: Complex Packaging for Sensitive Molecules
5) Neutral and Anionic Phospholipids
Unlike other lipid-based drug delivery (LBDD) systems, LNPs are complex structures with a typical particle size of approximately 50 to 150 nm. Their lipid components create a protective environment for sensitive nucleic acids such as mRNA, siRNA, and plasmid DNA (pDNA), enabling their efficient delivery into cells [4]. LNPs generally consist of ionizable lipids and various helper lipids, including glycerophospholipids, sterols, and PEGylated lipids (Fig. 1). Each of these components serves a specific function and contributes to the stability, structure, and overall properties of the LNPs [5]. By carefully selecting and combining different lipids, LNPs can be tailored to the specific application and the nucleic acid cargo to be delivered.
In addition to lipid composition, several other factors play a critical role in determining the properties and performance of LNPs. These include the molar ratio of the individual lipids, the lipid-to-nucleic acid weight ratio, the molar nitrogen-to-phosphate (N:P) ratio, the acid dissociation constant (pKa) of the ionizable lipid, particle size, and the route of administration, such as intravenous or intramuscular injection. These parameters can significantly affect the encapsulation efficiency, efficacy, toxicity, and pharmacokinetics of LNPs [5;6].
Ionizable cationic lipids can help reduce the cytotoxicity that may be associated with permanently positively charged cationic lipids. They contain functional groups that become protonated depending on the pH, thereby changing their charge. At low pH (typically <7), they are positively charged and can interact with negatively charged nucleic acids, facilitating their encapsulation within LNPs. At physiological pH, ionizable lipids are predominantly neutral or nearly neutral. This allows them to support the delivery of nucleic acids while reducing the nonspecific interactions with cell membranes and other biological structures that can occur with permanently positively charged lipids [5; 6].
| Lipid Name | Product Number | pKa Value of the Tertiary Amine |
| 1,2-Dioleoyl-3-dimethylammonium-propane (DODAP) | Cay25726 | 5,59 |
| 1,2-Dioleyloxy-3-dimethylamino-propane (DODMA) | Cay15109 | 6,59 |
| ALC-0315 | Cay34337 | 6,09 |
| DLin-MC3-DMA | Cay34364 | 6,44 |
| DLin-KC2-DMA | Cay34363 | 6,70 |
| SM-102 | Cay33474 | 6,68 |
Did you know? SM-102-based LNPs are well suited as a reference for the development and optimization of new LNP formulations due to their overall favorable properties and consistent performance. In this Technical Brief, Cayman Chemical presents data collected from multiple users over a one-year period. Different cargos were encapsulated using different batches of the respective lipid components to evaluate the performance of SM-102-based LNPs under various conditions.
Sterol lipids such as cholesterol are important components of LNPs. They influence the packing and fluidity of the lipid components and thereby contribute significantly to particle stability. In addition, they can affect the interaction of LNPs with cell membranes, supporting cellular uptake and subsequent processes such as endosomal escape. Some cholesterol derivatives, such as 7α-hydroxycholesterol, have also been used to improve the delivery efficiency of nucleic acid cargos [5; 6].
| Lipid Name | Product Number | Available Sizes |
| Cholesterol | Cay9003100 | 100 g, 250 g |
| 7α-hydroxy Cholesterol | Cay20098 | 1 mg, 5 mg, 10 mg, 25 mg |
Glycerophospholipids belong to the class of phospholipids. They consist of a hydrophilic head group and two hydrophobic fatty acid chains attached to a glycerol backbone. The chemical properties of the head group influence, among other things, the surface properties and charge of LNPs, which can be neutral, anionic (negative), or cationic (positive) depending on their composition [5; 6].
Neutral phospholipids can influence the membrane properties of LNPs and their interactions with cell membranes, thereby supporting efficient membrane fusion. Examples of phospholipids with an overall neutral charge include phosphatidylcholine (PC) and phosphatidylethanolamine (PE) [5].
Anionic lipids can be incorporated into LNP formulations to specifically modulate their surface properties and stability. In neutral LNP systems, they can help reduce particle aggregation during storage. In addition, they alter the net surface charge of LNPs and can thereby influence their interactions with cell membranes and other biological structures, as well as cellular targeting. Phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), and phosphatidic acid (PA) are examples of phospholipids with anionic head groups [5].
| Lipid Name | Product Nummer | Available Sizes |
| 1,2-Dioleoyl-sn-glycero-3-PE (1,2-DOPE) | Cay15091 | 100 mg, 250 mg, 500 mg |
| 1,2-Distearoyl-sn-glycero-3-PC (1,2-DSCP) | Cay15100 | 250 mg, 500 mg, 1 g |
| 1,2-Dioleoyl-sn-glycero-3-PC (1,2-DOPC) | Cay15098 | 250 mg, 500 mg, 1 g, 5 g |
| 1-Palmitoyl-2-Oleoyl-sn-glycero-3-PC (1,2-POPC) | Cay15102 | 100 mg, 250 mg, 500 mg |
| 1-Palmitoyl-2-Oleoyl-sn-glycero-3-PG (sodium salt) (1,2-POPG) | Cay15105 | 25 mg, 50 mg, 100 mg, 250 mg |
| 1,2-Dioleoyl-sn-glycero-3-PS (sodium salt) (1,2-DOPS) | Cay29983 | 5 mg, 10 mg, 25 mg, 50 mg |
PEGylated lipids reduce the adsorption of serum proteins to the surface of LNPs and can thereby decrease their uptake by the mononuclear phagocyte system (MPS) – an important factor in the delivery of lipid-based drug delivery (LBDD) systems. As a result, they can influence the stability and circulation time of LNPs in the body. Some PEGylated lipids also feature terminal functional groups, such as amino or maleimide groups. These enable the conjugation of additional molecules, such as ligands or targeting molecules, which can be used to specifically modulate the interaction of LNPs with particular cell types [5; 6].
| Lipid Name | Product Number | Available Sizes |
| DMG-PEG(2000) | Cay33945 | 500 mg, 1 g |
| ALC-0159 | Cay34336 | 25 mg, 50 mg, 100 mg, 500 mg |
LNPs are therefore far more than simple “balls of fat”: It is the interplay of different lipid components that makes them versatile delivery vehicles for sensitive nucleic acids. But how are these complex particles actually produced – and what options are available for using LNPs in your own research? Find out in the second part of our LNP series.
Curious to learn more? Explore the complete Cayman Chemical portfolio or discover more about LNPs on our blog!
[1] Ogris, M., & Wagner, E. (2011). To be targeted: is the magic bullet concept a viable option for synthetic nucleic acid therapeutics?. Human gene therapy, 22(7), 799–807.
[2] https://www.merckgroup.com/de/research/science-space/envisioning-tomorrow/lipid-nanoparticles.html, 13.08.2026
[3] https://www.pharmazeutische-zeitung.de/sensible-molekuele-komplex-verpackt-123339/, 13.08.2026
[4] Mendes, B.B., Conniot, J., Avital, A. et al. Nanodelivery of nucleic acids. Nat Rev Methods Primers 2, 24 (2022).
[6] Hou, X., Zaks, T., Langer, R. et al. Lipid nanoparticles for mRNA delivery. Nat Rev Mater 6, 1078–1094 (2021).
Preview Image: https://www.caymanchem.com/lipid-nanoparticles