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The Role of Helper Lipids in Lipid Nanoparticles

Lipid nanoparticles are the most advanced RNA drug delivery system in the clinic. What are helper lipids? Whats the role of helper lipids in lipid nanoparticles?

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The Role of Helper Lipids in Lipid Nanoparticles

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  1. Huateng Pharma https://us.huatengsci.com The Role of Helper Lipids in Lipid Nanoparticles Lipid nanoparticles are the most advanced RNA drug delivery system in the clinic. In 2018, the first siRNA LNP drug, ONPATTRO, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR). More recently, similar LNPs have been used to deliver mRNA encoding the SARS-Cov-2 viral spike protein to vaccinate billions of people against COVID-19 via intramuscular injection. All three FDA-approved LNPS have similar four-component LNPs. Figure 1. Moderna and Pfizer/BioNtech FDA approved COVID-19 vaccine utilizing LNPs share similar 4 components to ONPATTRO. All the current FDA-approved LNP formulations contain four lipids: (1) an ionizable cationic lipid, helper lipids which include (2) phospholipid (3) cholesterol, and (4) a PEG-lipid conjugate. These components facilitate monodisperse nanoparticle formation, improve nanoparticle stability, enable efficient nucleic acid encapsulation, assist cellular uptake, and promote endosomal escape of nucleic acid drugs. This complex yet specific structure confers LNP with significantly better characteristics than other delivery platforms, including greater tissue penetration, higher transfection efficiency and nucleic acid encapsulation rate, and lower cytotoxicity.

  2. Huateng Pharma https://us.huatengsci.com Figure 2. Components of LNPs, source: reference [1] Role of Helper Lipids in LNPs Each helper lipid of LNPs exerts a different function in LNP drug delivery system. Role of PEG Lipids in LNPs The PEG-lipid component is a crucial component for the formulation of LNPs and serves a multitude of purposes. 1) Promote stability by preventing particle aggregation, prolonging half-life in the bloodstream, and preventing immune system recognition. 2) The molecular weight and the molar percentage of the PEG lipid can affect the characteristics of LNPs and its physiochemical properties. 3) The length of the acyl chain tail is correlate with dissociation of the PEG lipid from the LNP surface in circulation, which is especially important in the context of delivery to target tissues or cells due to protein recognition that occurs when LNPs are in systemic circulation. It is has been shown that PEG lipids with shorter carbon acyl chains dissociate rapidly from the LNP in circulation in comparison to PEG lipids with longer carbon acyl chains. However, PEGylation also presents a "PEG dilemma" that hinders interaction with target cells and subsequent endosomal escape, resulting in reduced transfection efficiency. Huateng Pharma is able to provide the PEG products for your mRNA delivery from mg to kg. PEG linkers with molecular weights and functional groups not listed in our online catalog may be available by custom synthesis.

  3. Huateng Pharma https://us.huatengsci.com Figure 3. Examples of sterols (green), phospholipids (blue), and PEG-lipids (red) used in LNP formulations. Source: reference [2] Role of Cholesterols in LNPs LNP formulations usually have between 35-45% composition with respect to cholesterol. Cholesterol can enhance the stability of lipid nanoparticles, assist membrane fusion, and facilitate the entry of mRNA into cytoplasm. Traditionally, cholesterol - even pharmacopoeia-grade cholesterol - has been derived from natural animal sources, preferably lanolin ( sheep's wool grease). However, there are several risks associated with animal-sourced products, such as the transmission of diseases such as TSE, unwanted immune reactions or fluctuations in product quality. The invention of a synthetic method for extracting cholesterol from plant-derived phytosterols has made possible the mass production of excipient-grade cholesterol that is completely free of animal components, with a high and consistent product quality that meets pharmacopoeial requirements. Huateng Pharma can provide plant-derived Cholesterol from gram to multi-kilogram scale.

  4. Huateng Pharma https://us.huatengsci.com Role of Phospholipids in LNPs Phospholipids help encapsulate nucleic acids and stabilize LNP. They are relatively less studied than other lipid components and typically account for only 10-20% of the total lipids in a formulation. Phospholipids are used as structural lipids due to their spontaneous organization into lipid bilayers and high phase transition temperatures, which confer membrane stability to LNP. Like cell membranes, phospholipids are located at the periphery of the LNP. These lipids are usually semisynthetic. For example, phosphatidylcholine is usually derived from natural sources such as egg yolk and soybeans and can be chemically modified to include fatty acid tails. 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) is a structural lipid used in clinically approved LNPs such as siRNA therapeutics (Onpattro) and mRNA vaccines against SARS-CoV-2. DSPC is structurally composed of a phosphatidylcholine head group and two saturated 18-carbon tails, forming a tightly stacked lipid bilayer. In LNP, it is predominantly located on the surface of the nanoparticles and secondarily in the core of the nanoparticles. 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) is another phospholipid that is often used in preclinical studies of LNP.The unsaturated tails of DOPE form a more fluid lipid bilayer. Lipid supplier and customer synthesis As a leading biochemical supplier worldwide, Huateng Pharma offer a wide array of Lipid molecules, such as plant-derived Cholesterol, DSPE, PEG lipids to our clients worldwide. Huateng Pharma also provides fast speed custom synthesis of novel lipid molecules to empower your advanced research. References: [1] C. H. Albertsena, J. A.Kulkarnib, D. Witzigmann, The role of lipid components in lipid nanoparticles for vaccines and gene therapy. Advanced Drug Delivery Reviews, 2022. [2] Eygeris Y, Gupta M, Kim J, Sahay G. Chemistry of Lipid Nanoparticles for RNA Delivery. Acc Chem Res. 2022;55(1):2-12. doi:10.1021/acs.accounts.1c00544. Related Articles Lipid-Based Nanoparticles: Liposomes VS. Lipid nanoparticles (LNPs) Lipid Nanoparticles (LNP) for mRNA Drug Delivery What Are PEG Linkers and Their Applications?

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