SlideShare a Scribd company logo
1 of 8
Download to read offline
Biopharma PEG https://www.biochempeg.com
The Role of Four Lipid Components Of LNPs
Lipid nanoparticles (LNPs) play an important role in COVID-19 mRNA vaccines. In
addition, many preclinical and clinical studies have shown that LNPs have great potential
in the field of nucleic acid therapy. The structural and biological properties of LNPs are not
solely attributable to a single lipid component, but rather a combination of various types of
lipids. Therefore, we will focus on describing the role of different lipid components in LNP
preparation.
Lipid Components of LNPs
Generally, LNP consists of four components: ionizable cationic lipids,
phospholipids, cholesterol, and PEG lipids (Figure 1). Each component plays a key
role in terms of LNP stability, transfection efficacy and safety.
Figure 1. Components of LNPs
Biopharma PEG https://www.biochempeg.com
Ionizable Cationic Lipids
Ionizable cationic lipids are key components in the LNP formulation, and their acid
dissociation constants (pKa) determine the ionization and surface charge of LNP,
further affecting its stability and toxicity. Conventional permanently charged cationic
lipids previously used for nucleic acid delivery (e.g., DOTAP) readily interact with
negatively charged serum proteins and aggregate in the bloodstream, which can lead to
rapid clearance of LNP by mononuclear phagocytes, resulting in a short half-life in the
bloodstream. In addition, the relatively high hemolytic activity of cationic lipids increases
the risk of toxic side effects, such as hemoglobin release due to red cell membrane
damage. To avoid these problems, ionizable cationic lipids with pKa values typically
ranging from 6.0 to 7.0 have been developed. This ionizable lipid-based LNP (iLNP)
ensures efficient encapsulation of nucleic acids under acidic conditions and
reduces toxicity during recycling under physiological conditions. Entering
endosomes/lysosomes (pH below surface pKa), LNP can be positively charged again to
facilitate endosome escape and release mRNA into the cytoplasm. It was found that LNP
with pKa values of 6.2-6.5 and 6.6-6.9 favored hepatic delivery of siRNA in vivo and
intramuscular administration of mRNA vaccines, respectively.
Structurally, synthetic lipids usually contain three parts: (i) cationic or ionizable head
groups, (ii) linker groups, and (iii) hydrophobic tails. The chemical diversity of each part
results in a number of structurally distinct ionizable lipids that can be produced by
combinatorial chemistry. Depending on the number of amino heads, ionizable cationic
lipids can be classified as either monoamino or polyamino lipids. DLin-MC3-DMA (MC3),
SM-102, and ALC-0315 are the best known monoamino acid lipids. They are also the
three FDA-approved ionizable cationic lipids for RNA delivery. Researchers usually focus
on tuning the lipid tail structure to confer enhanced potency or specific functions by
changing the number of tails, designing linear or branching structures, and introducing
unsaturated or biodegradable bonds, e.g., the unsaturated tails in MC3 and ester bonds in
L319 play important roles in facilitating endosomal escape of siRNAs and accelerating
intracellular degradation of lipids. By providing larger head groups, polyamino-ionizable
cationic lipids have greater variability than monoamino-ionizable cationic lipids, and a
Biopharma PEG https://www.biochempeg.com
number of multitude of lipids have been designed and studied, e.g., 306O i10, cKK-E12,
C12-200, 5A2-SC8, TT3, FTT5.
Figure 2. The ionizable lipids used Comirnaty® (ALC-0315) and Spikevax® (SM-102) and
in Onpattro® (MC3). Source: reference [1]
PEG-lipids
Even though PEG-lipids constitute the smallest molar percentage of the lipid components
in LNPs (typically ∼1.5 mol%), they have several effects on the properties of lipid
nanoparticles.
 1. The amount of PEG-lipids can influence particle size and zeta potential;
 2. PEG-lipids can better contribute to particle stability by decreasing particle aggregation;
 3. Certain PEG modifications extend the blood circulation time of nanoparticles by
lowering clearance mediated by the kidneys and the mononuclear phagocyte system
(MPS).
 4. PEG-lipids can be used to conjugate particular ligands to the particle for targeted
delivery.
The short chained diacyl PEG-lipid PEG-carbamate-1,2-dimyristoyl-sn-glycerol
(PEG-c-DMG) is introduced in the Onpattro® formulation, which is rapidly dissociated
from the lipid membrane. When dissociated from their PEG, LNPs can interact with blood
proteins, including ApoE proteins, for delivery to the hepatocytes. In this context, two short
lipids-PEG (C14) were recently used in the Comirnaty® and Spikevax® COVID-19
vaccines: ALC-0159 (DTA-PEG2000, ditetradecylacetamide) and DMG-PEG2000,
respectively.
Biopharma PEG https://www.biochempeg.com
Figure 3. The PEG-lipids used in Onpattro® (PEG-c-DMG) , Spikevax® (PEG-DMG) and
Comirnaty® (ALC-0159). Source: reference [1]
However, PEGylation also presents a "PEG dilemma" that hinders interaction with
target cells and subsequent endosomal escape, resulting in reduced transfection
efficiency.
Accelerated blood clearance ("ABC phenomenon") is an unexpected immunogenic
response observed in PEG conjugates that results in rapid clearance of PEGylated
nanocarriers. The ABC phenomenon has been widely observed after repeated dosing and
reduces the effectiveness of PEG conjugates and nanocarriers.
Another unexpected immune response is the hypersensitivity reaction known
as complement activation-related pseudoallergy (CARPA), which significantly
reduces the safety of PEGylated nanocarriers and has been associated with reduced
efficacy of PEGylated treatments in clinical trials. The CARPA phenomenon has been
categorized as a non-IgE-mediated pseudoallergic reaction caused by activation of the
complement system.
Various parameters of the PEG–lipid chemical structure including PEG size and
architecture, lipid structure including hydrocarbon chains, headgroup, lipid–PEG linkage,
and PEG terminal groups, are significant determinants of the PEGylated LNPs safety and
bioactivity.
Biopharma PEG https://www.biochempeg.com
Figure 3. Scheme of the PEG–lipid structure. Source: reference [3]
 ▶ PEG length is a key structural factor influencing the immunologic safety profile. The
effect is biphasic, with both long and short chain PEG conjugates being more likely to
induce the ABC phenomenon.
 ▶ Like PEG length, PEG density (i.e., the percentage of PEG in the LNP) also exhibits a
biphasic effect. However, both lower and higher densities of PEG exhibit a reduced ABC
phenomenon.
 ▶ Differences in PEG structure may have an effect, with branched PEG lipid conjugates
conferring a higher degree of invisibility to LNP compared to linear PEG.
 ▶ The functional terminal groups attached to the chain of the PEG particles are another
factor that affects their immunogenicity and clearance.
 ▶ Parameters such as size and surface charge also affect immunogenicity. For example,
PEGylated carriers containing negatively charged phospholipids are more capable of
stimulating the immune system through complement activation than uncharged vesicles.
 ▶ As with the PEG fraction, the structure and length of the hydrophobic chains of lipids can
determine not only the degree of immunogenicity but also its efficacy.
 ▶ PEGylated LNP produced using a specific lipid anchoring group (e.g., cholesterol as an
anchoring group) has more sustained permeability and higher systemic bioavailability in
circulation.
 ▶ Lipid linkage is an important parameter in the design and performance of lipids, where
ester bonds replace carbamate bonds for the formation of unstable vesicles.
Biopharma PEG https://www.biochempeg.com
A thorough understanding of the correlation between the structural parameters of PEG
lipids and the immune-related adverse effects of PEGylated LNPs, as well as their
biophysical and physiological background, is an essential requirement. With this
knowledge, optimal drug formulations that reduce and eliminate adverse immune
reactions and improve the safety and efficiency of PEGylated drugs can be prepared.
Helper Lipids - Cholesterol
The inclusion of cholesterol in nucleic acid-containing LNP formulations is based primarily
on two major findings obtained with liposomal formulations of small molecule therapeutics:
1) cholesterol is an exchangeable molecule that can accumulate within liposomes during
circulation, 2) cholesterol dramatically reduces the amount of surface-bound proteins and
improves the circulating half-life. Therefore, equimolar amounts of cholesterol are
included in LNP formulations relative to endogenous membranes; this prevents net efflux
or influx and maintains membrane integrity.
Lipids such as cholesterol are also essential for encapsulating nucleic acids. Since
cholesterol increases membrane rigidity, it reduces drug leakage from the liposomal core.
However, for large cargo such as nucleic acids, this effect may not be important. As the
design of ionizable lipids has improved, providing more potency and less toxicity, the total
proportion of helper lipid has decreased. However, a recent study noted that a certain
threshold amount of helper lipids is still needed to promote stable encapsulation.
Biopharma PEG can supply high-quality cholesterol (plant-derived) from lab to large
scale to meet your research and drug development needs.
Biopharma PEG https://www.biochempeg.com
Figure 4. The molecular shape of standard helper lipids, including DSPC, DOPE, and
cholesterol, used in LNPs. Source: reference [1]
Helper Lipids – Phospholipids
Phospholipids are helper lipids that contribute to the formation of lipid nanoparticles and
the escape of endosomes. Commonly used phospholipids in preclinical studies and
clinical applications are DSPC and DOPE. Phospholipids can spontaneously organize
into lipid bilayers and the higher phase transition temperature enhances the membrane
stability of LNPs. Similar to 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 (e.g., by adding fatty acid tails).
DSPC is a structural lipid used in LNPs for siRNA therapy (Onpattro) and SARS-CoV-2
mRNA vaccines. DSPC consists of a phosphatidylcholine head group and two saturated
18-carbon tails, with the two tails forming a tightly packed lipid bilayer. In LNP, DSPC is
mainly located on the surface of the nanoparticles and in more marginal positions in the
core of the nanoparticles. DOPE is another phospholipid commonly used in preclinical
studies of LNP. The unsaturated tails of DOPE not only form a more fluid lipid bilayer but
also are capable of forming a hexagonal-phase (HII) organized form, which facilitates the
fusion of lipid membranes with endosomal membranes, leading to cytoplasmic nucleic
acid release.
Biopharma PEG https://www.biochempeg.com
Conclusion
Under the premise of consistent preparation conditions, the nucleic acid composition and
the proportion of lipids have a decisive influence on the structure of nanoparticles.
Understanding the function of various types of lipids is a prerequisite for the optimization
of LNP formulations, and the roles of four common components of LNPs are briefly
described in the paper.
Biopharma PEG is a dynamic science company dedicated to PEG derivatives. We are
capable of supplying small to large quantities of a rich selection of PEG derivatives with
GMP & non-GMP standards for your mRNA vaccine R&D. We can produce and provide
classic PEG lipids, such as mPEG-DMG, ALC-0159 and mPEG-DSPE for your LNPs
R&D.
References:
[1] Hald Albertsen C, Kulkarni JA, Witzigmann D, Lind M, Petersson K, Simonsen JB. The
role of lipid components in lipid nanoparticles for vaccines and gene therapy. Adv Drug
Deliv Rev. 2022 Sep;188:114416. doi: 10.1016/j.addr.2022.114416. Epub 2022 Jul 3.
PMID: 35787388; PMCID: PMC9250827.
[2] Hou, X., Zaks, T., Langer, R. et al. Lipid nanoparticles for mRNA delivery. Nat Rev
Mater 6, 1078–1094 (2021). https://doi.org/10.1038/s41578-021-00358-0
[3] PEGylated Lipid Nanoparticle Formulations: Immunological Safety and Efficiency
Perspective, Rumiana Tenchov, Janet M. Sasso, and Qiongqiong Angela Zhou,
Bioconjugate Chemistry 2023 34 (6), 941-960, DOI: 10.1021/acs.bioconjchem.3c00174
Related Articles:
Application of Lipid Nanoparticles In Vaccine And Drug Delivery
Liposomes vs. Lipid Nanoparticles: Which Is Best for Drug Delivery?
Lipid nanoparticles (LNPs) In Cancer Immunotherapy
PEGylated Liposomes in the Clinic and Clinical Trials

More Related Content

Similar to The Role of Four Lipid Components Of LNPs.pdf

mRNA Technology How To Achieve Targeted Delivery to Organs, Cells, Tumors.pdf
mRNA Technology How To Achieve Targeted Delivery to Organs, Cells, Tumors.pdfmRNA Technology How To Achieve Targeted Delivery to Organs, Cells, Tumors.pdf
mRNA Technology How To Achieve Targeted Delivery to Organs, Cells, Tumors.pdfDoriaFang
 
Liposomal gene delivery system
Liposomal gene delivery systemLiposomal gene delivery system
Liposomal gene delivery systemDurga Bhavani
 
Prospects And Future Trend of mRNA Therapeutics.pdf
Prospects And Future Trend of mRNA Therapeutics.pdfProspects And Future Trend of mRNA Therapeutics.pdf
Prospects And Future Trend of mRNA Therapeutics.pdfDoriaFang
 
PEGylation technique
PEGylation techniquePEGylation technique
PEGylation techniqueKushal Saha
 
Lipid rafts an overview
Lipid rafts an overviewLipid rafts an overview
Lipid rafts an overviewJaiKumar377
 
Recent Advancement and Patents of the Lipid Polymer Hybrid Nanoparticles
Recent Advancement and Patents of the Lipid Polymer Hybrid NanoparticlesRecent Advancement and Patents of the Lipid Polymer Hybrid Nanoparticles
Recent Advancement and Patents of the Lipid Polymer Hybrid Nanoparticlespeertechzpublication
 
SEMINAR II FINAL.pptx
 SEMINAR II FINAL.pptx SEMINAR II FINAL.pptx
SEMINAR II FINAL.pptxssuser4fe6eb1
 
co and post translation modification, by
co and post translation modification, byco and post translation modification, by
co and post translation modification, byKAUSHAL SAHU
 
Advances in siRNA Drug Research.doc
Advances in siRNA Drug Research.docAdvances in siRNA Drug Research.doc
Advances in siRNA Drug Research.docZoeZoe46
 
Preparation of protein-loaded PLGA-PVP blend nanoparticles by nanoprecipitati...
Preparation of protein-loaded PLGA-PVP blend nanoparticles by nanoprecipitati...Preparation of protein-loaded PLGA-PVP blend nanoparticles by nanoprecipitati...
Preparation of protein-loaded PLGA-PVP blend nanoparticles by nanoprecipitati...Nanomedicine Journal (NMJ)
 
Strategies, Modifications, and Materials for RNA Delivery In Vitro and In Vivo
Strategies, Modifications, and Materials for RNA Delivery In Vitro and In VivoStrategies, Modifications, and Materials for RNA Delivery In Vitro and In Vivo
Strategies, Modifications, and Materials for RNA Delivery In Vitro and In Vivoshrutivarode
 
New Progress of Targeted Degradation Based On Nucleic Acid.pdf
New Progress of Targeted Degradation Based On Nucleic Acid.pdfNew Progress of Targeted Degradation Based On Nucleic Acid.pdf
New Progress of Targeted Degradation Based On Nucleic Acid.pdfDoriaFang
 

Similar to The Role of Four Lipid Components Of LNPs.pdf (20)

GPI real.ppt
GPI real.pptGPI real.ppt
GPI real.ppt
 
Modified liposomes
Modified liposomesModified liposomes
Modified liposomes
 
mRNA Technology How To Achieve Targeted Delivery to Organs, Cells, Tumors.pdf
mRNA Technology How To Achieve Targeted Delivery to Organs, Cells, Tumors.pdfmRNA Technology How To Achieve Targeted Delivery to Organs, Cells, Tumors.pdf
mRNA Technology How To Achieve Targeted Delivery to Organs, Cells, Tumors.pdf
 
Liposomal gene delivery system
Liposomal gene delivery systemLiposomal gene delivery system
Liposomal gene delivery system
 
Final GSK John A L Short Report
Final GSK John A L Short ReportFinal GSK John A L Short Report
Final GSK John A L Short Report
 
Prospects And Future Trend of mRNA Therapeutics.pdf
Prospects And Future Trend of mRNA Therapeutics.pdfProspects And Future Trend of mRNA Therapeutics.pdf
Prospects And Future Trend of mRNA Therapeutics.pdf
 
mRNA vaccines.pptx
mRNA vaccines.pptxmRNA vaccines.pptx
mRNA vaccines.pptx
 
PEGylation technique
PEGylation techniquePEGylation technique
PEGylation technique
 
Lipid rafts an overview
Lipid rafts an overviewLipid rafts an overview
Lipid rafts an overview
 
Recent Advancement and Patents of the Lipid Polymer Hybrid Nanoparticles
Recent Advancement and Patents of the Lipid Polymer Hybrid NanoparticlesRecent Advancement and Patents of the Lipid Polymer Hybrid Nanoparticles
Recent Advancement and Patents of the Lipid Polymer Hybrid Nanoparticles
 
Open Journal of Chemistry
Open Journal of ChemistryOpen Journal of Chemistry
Open Journal of Chemistry
 
SEMINAR II FINAL.pptx
 SEMINAR II FINAL.pptx SEMINAR II FINAL.pptx
SEMINAR II FINAL.pptx
 
Presentation
PresentationPresentation
Presentation
 
co and post translation modification, by
co and post translation modification, byco and post translation modification, by
co and post translation modification, by
 
Polycaprolactone(PCL)
Polycaprolactone(PCL)Polycaprolactone(PCL)
Polycaprolactone(PCL)
 
Advances in siRNA Drug Research.doc
Advances in siRNA Drug Research.docAdvances in siRNA Drug Research.doc
Advances in siRNA Drug Research.doc
 
Peroxisomes in dermatology
Peroxisomes in dermatologyPeroxisomes in dermatology
Peroxisomes in dermatology
 
Preparation of protein-loaded PLGA-PVP blend nanoparticles by nanoprecipitati...
Preparation of protein-loaded PLGA-PVP blend nanoparticles by nanoprecipitati...Preparation of protein-loaded PLGA-PVP blend nanoparticles by nanoprecipitati...
Preparation of protein-loaded PLGA-PVP blend nanoparticles by nanoprecipitati...
 
Strategies, Modifications, and Materials for RNA Delivery In Vitro and In Vivo
Strategies, Modifications, and Materials for RNA Delivery In Vitro and In VivoStrategies, Modifications, and Materials for RNA Delivery In Vitro and In Vivo
Strategies, Modifications, and Materials for RNA Delivery In Vitro and In Vivo
 
New Progress of Targeted Degradation Based On Nucleic Acid.pdf
New Progress of Targeted Degradation Based On Nucleic Acid.pdfNew Progress of Targeted Degradation Based On Nucleic Acid.pdf
New Progress of Targeted Degradation Based On Nucleic Acid.pdf
 

More from DoriaFang

Cyclic Peptides Current Status & Future Prospects.pdf
Cyclic Peptides Current Status & Future Prospects.pdfCyclic Peptides Current Status & Future Prospects.pdf
Cyclic Peptides Current Status & Future Prospects.pdfDoriaFang
 
Antibody–Oligonucleotide Conjugates (AOCs) in Clinical Trials.pdf
Antibody–Oligonucleotide Conjugates (AOCs) in Clinical Trials.pdfAntibody–Oligonucleotide Conjugates (AOCs) in Clinical Trials.pdf
Antibody–Oligonucleotide Conjugates (AOCs) in Clinical Trials.pdfDoriaFang
 
Alzheimer's Disease Drug Development Aducanumab, Lecanemab & Donanemab.pdf
Alzheimer's Disease Drug Development Aducanumab, Lecanemab & Donanemab.pdfAlzheimer's Disease Drug Development Aducanumab, Lecanemab & Donanemab.pdf
Alzheimer's Disease Drug Development Aducanumab, Lecanemab & Donanemab.pdfDoriaFang
 
Claudin6 (CLDN6) A Emerging Target For Solid Tumor.pdf
Claudin6 (CLDN6) A Emerging Target For Solid Tumor.pdfClaudin6 (CLDN6) A Emerging Target For Solid Tumor.pdf
Claudin6 (CLDN6) A Emerging Target For Solid Tumor.pdfDoriaFang
 
ROR1 ADCs in Clinical Trials MK-2140, NBE-002 & CS5001.pdf
ROR1 ADCs in Clinical Trials MK-2140, NBE-002 & CS5001.pdfROR1 ADCs in Clinical Trials MK-2140, NBE-002 & CS5001.pdf
ROR1 ADCs in Clinical Trials MK-2140, NBE-002 & CS5001.pdfDoriaFang
 
Summary of Targeted Protein Degradation in Clinical Trials.pdf
Summary of Targeted Protein Degradation in Clinical Trials.pdfSummary of Targeted Protein Degradation in Clinical Trials.pdf
Summary of Targeted Protein Degradation in Clinical Trials.pdfDoriaFang
 
Overview of New Targets For Anti-tumor Drugs.pdf
Overview of New Targets For Anti-tumor Drugs.pdfOverview of New Targets For Anti-tumor Drugs.pdf
Overview of New Targets For Anti-tumor Drugs.pdfDoriaFang
 
Cleavable Linkers Used In ADC Development.pdf
Cleavable Linkers Used In ADC Development.pdfCleavable Linkers Used In ADC Development.pdf
Cleavable Linkers Used In ADC Development.pdfDoriaFang
 
Trophoblast Glycoprotein (TPGB5T4) A New Target For ADC Drugs.pdf
Trophoblast Glycoprotein (TPGB5T4) A New Target For ADC Drugs.pdfTrophoblast Glycoprotein (TPGB5T4) A New Target For ADC Drugs.pdf
Trophoblast Glycoprotein (TPGB5T4) A New Target For ADC Drugs.pdfDoriaFang
 
Advances in TROP-2 Directed ADCs.pdf
Advances in TROP-2 Directed ADCs.pdfAdvances in TROP-2 Directed ADCs.pdf
Advances in TROP-2 Directed ADCs.pdfDoriaFang
 
DS-8201 (Enhertu) A Potential ADC Drug Targeting HER2.pdf
DS-8201 (Enhertu) A Potential ADC Drug Targeting HER2.pdfDS-8201 (Enhertu) A Potential ADC Drug Targeting HER2.pdf
DS-8201 (Enhertu) A Potential ADC Drug Targeting HER2.pdfDoriaFang
 
List of New Anti-cancer Drugs Approved By FDA In The First Half of 2023.pdf
List of New Anti-cancer Drugs Approved By FDA In The First Half of 2023.pdfList of New Anti-cancer Drugs Approved By FDA In The First Half of 2023.pdf
List of New Anti-cancer Drugs Approved By FDA In The First Half of 2023.pdfDoriaFang
 
Overview of Oral Delivery Strategies for Peptides.pdf
Overview of Oral Delivery Strategies for Peptides.pdfOverview of Oral Delivery Strategies for Peptides.pdf
Overview of Oral Delivery Strategies for Peptides.pdfDoriaFang
 
The Future Development of ADC For Cancer.pdf
The Future Development of ADC For Cancer.pdfThe Future Development of ADC For Cancer.pdf
The Future Development of ADC For Cancer.pdfDoriaFang
 
Summary of ADC Targets For Solid Tumors & Hematological Tumors.pdf
Summary of ADC Targets For Solid Tumors & Hematological Tumors.pdfSummary of ADC Targets For Solid Tumors & Hematological Tumors.pdf
Summary of ADC Targets For Solid Tumors & Hematological Tumors.pdfDoriaFang
 
New Oncology Trends ADCs, Bispecific Antibodies & CAR-T Cell.pdf
New Oncology Trends ADCs, Bispecific Antibodies & CAR-T Cell.pdfNew Oncology Trends ADCs, Bispecific Antibodies & CAR-T Cell.pdf
New Oncology Trends ADCs, Bispecific Antibodies & CAR-T Cell.pdfDoriaFang
 
Summary of Treatments for Multiple Myeloma.pdf
Summary of Treatments for Multiple Myeloma.pdfSummary of Treatments for Multiple Myeloma.pdf
Summary of Treatments for Multiple Myeloma.pdfDoriaFang
 
Bispecific Antibody-drug Conjugate Drugs In Clinical or Preclinical.pdf
Bispecific Antibody-drug Conjugate Drugs In Clinical or Preclinical.pdfBispecific Antibody-drug Conjugate Drugs In Clinical or Preclinical.pdf
Bispecific Antibody-drug Conjugate Drugs In Clinical or Preclinical.pdfDoriaFang
 
ADCs Targeting the HER Family.pdf
ADCs Targeting the HER Family.pdfADCs Targeting the HER Family.pdf
ADCs Targeting the HER Family.pdfDoriaFang
 
Nectin-4 New Antibody-Drug Conjugate (ADC) Target.pdf
Nectin-4 New Antibody-Drug Conjugate (ADC) Target.pdfNectin-4 New Antibody-Drug Conjugate (ADC) Target.pdf
Nectin-4 New Antibody-Drug Conjugate (ADC) Target.pdfDoriaFang
 

More from DoriaFang (20)

Cyclic Peptides Current Status & Future Prospects.pdf
Cyclic Peptides Current Status & Future Prospects.pdfCyclic Peptides Current Status & Future Prospects.pdf
Cyclic Peptides Current Status & Future Prospects.pdf
 
Antibody–Oligonucleotide Conjugates (AOCs) in Clinical Trials.pdf
Antibody–Oligonucleotide Conjugates (AOCs) in Clinical Trials.pdfAntibody–Oligonucleotide Conjugates (AOCs) in Clinical Trials.pdf
Antibody–Oligonucleotide Conjugates (AOCs) in Clinical Trials.pdf
 
Alzheimer's Disease Drug Development Aducanumab, Lecanemab & Donanemab.pdf
Alzheimer's Disease Drug Development Aducanumab, Lecanemab & Donanemab.pdfAlzheimer's Disease Drug Development Aducanumab, Lecanemab & Donanemab.pdf
Alzheimer's Disease Drug Development Aducanumab, Lecanemab & Donanemab.pdf
 
Claudin6 (CLDN6) A Emerging Target For Solid Tumor.pdf
Claudin6 (CLDN6) A Emerging Target For Solid Tumor.pdfClaudin6 (CLDN6) A Emerging Target For Solid Tumor.pdf
Claudin6 (CLDN6) A Emerging Target For Solid Tumor.pdf
 
ROR1 ADCs in Clinical Trials MK-2140, NBE-002 & CS5001.pdf
ROR1 ADCs in Clinical Trials MK-2140, NBE-002 & CS5001.pdfROR1 ADCs in Clinical Trials MK-2140, NBE-002 & CS5001.pdf
ROR1 ADCs in Clinical Trials MK-2140, NBE-002 & CS5001.pdf
 
Summary of Targeted Protein Degradation in Clinical Trials.pdf
Summary of Targeted Protein Degradation in Clinical Trials.pdfSummary of Targeted Protein Degradation in Clinical Trials.pdf
Summary of Targeted Protein Degradation in Clinical Trials.pdf
 
Overview of New Targets For Anti-tumor Drugs.pdf
Overview of New Targets For Anti-tumor Drugs.pdfOverview of New Targets For Anti-tumor Drugs.pdf
Overview of New Targets For Anti-tumor Drugs.pdf
 
Cleavable Linkers Used In ADC Development.pdf
Cleavable Linkers Used In ADC Development.pdfCleavable Linkers Used In ADC Development.pdf
Cleavable Linkers Used In ADC Development.pdf
 
Trophoblast Glycoprotein (TPGB5T4) A New Target For ADC Drugs.pdf
Trophoblast Glycoprotein (TPGB5T4) A New Target For ADC Drugs.pdfTrophoblast Glycoprotein (TPGB5T4) A New Target For ADC Drugs.pdf
Trophoblast Glycoprotein (TPGB5T4) A New Target For ADC Drugs.pdf
 
Advances in TROP-2 Directed ADCs.pdf
Advances in TROP-2 Directed ADCs.pdfAdvances in TROP-2 Directed ADCs.pdf
Advances in TROP-2 Directed ADCs.pdf
 
DS-8201 (Enhertu) A Potential ADC Drug Targeting HER2.pdf
DS-8201 (Enhertu) A Potential ADC Drug Targeting HER2.pdfDS-8201 (Enhertu) A Potential ADC Drug Targeting HER2.pdf
DS-8201 (Enhertu) A Potential ADC Drug Targeting HER2.pdf
 
List of New Anti-cancer Drugs Approved By FDA In The First Half of 2023.pdf
List of New Anti-cancer Drugs Approved By FDA In The First Half of 2023.pdfList of New Anti-cancer Drugs Approved By FDA In The First Half of 2023.pdf
List of New Anti-cancer Drugs Approved By FDA In The First Half of 2023.pdf
 
Overview of Oral Delivery Strategies for Peptides.pdf
Overview of Oral Delivery Strategies for Peptides.pdfOverview of Oral Delivery Strategies for Peptides.pdf
Overview of Oral Delivery Strategies for Peptides.pdf
 
The Future Development of ADC For Cancer.pdf
The Future Development of ADC For Cancer.pdfThe Future Development of ADC For Cancer.pdf
The Future Development of ADC For Cancer.pdf
 
Summary of ADC Targets For Solid Tumors & Hematological Tumors.pdf
Summary of ADC Targets For Solid Tumors & Hematological Tumors.pdfSummary of ADC Targets For Solid Tumors & Hematological Tumors.pdf
Summary of ADC Targets For Solid Tumors & Hematological Tumors.pdf
 
New Oncology Trends ADCs, Bispecific Antibodies & CAR-T Cell.pdf
New Oncology Trends ADCs, Bispecific Antibodies & CAR-T Cell.pdfNew Oncology Trends ADCs, Bispecific Antibodies & CAR-T Cell.pdf
New Oncology Trends ADCs, Bispecific Antibodies & CAR-T Cell.pdf
 
Summary of Treatments for Multiple Myeloma.pdf
Summary of Treatments for Multiple Myeloma.pdfSummary of Treatments for Multiple Myeloma.pdf
Summary of Treatments for Multiple Myeloma.pdf
 
Bispecific Antibody-drug Conjugate Drugs In Clinical or Preclinical.pdf
Bispecific Antibody-drug Conjugate Drugs In Clinical or Preclinical.pdfBispecific Antibody-drug Conjugate Drugs In Clinical or Preclinical.pdf
Bispecific Antibody-drug Conjugate Drugs In Clinical or Preclinical.pdf
 
ADCs Targeting the HER Family.pdf
ADCs Targeting the HER Family.pdfADCs Targeting the HER Family.pdf
ADCs Targeting the HER Family.pdf
 
Nectin-4 New Antibody-Drug Conjugate (ADC) Target.pdf
Nectin-4 New Antibody-Drug Conjugate (ADC) Target.pdfNectin-4 New Antibody-Drug Conjugate (ADC) Target.pdf
Nectin-4 New Antibody-Drug Conjugate (ADC) Target.pdf
 

Recently uploaded

Shots fired Budget Presentation.pdf12312
Shots fired Budget Presentation.pdf12312Shots fired Budget Presentation.pdf12312
Shots fired Budget Presentation.pdf12312LR1709MUSIC
 
Future of Trade 2024 - Decoupled and Reconfigured - Snapshot Report
Future of Trade 2024 - Decoupled and Reconfigured - Snapshot ReportFuture of Trade 2024 - Decoupled and Reconfigured - Snapshot Report
Future of Trade 2024 - Decoupled and Reconfigured - Snapshot ReportDubai Multi Commodity Centre
 
Innomantra Viewpoint - Building Moonshots : May-Jun 2024.pdf
Innomantra Viewpoint - Building Moonshots : May-Jun 2024.pdfInnomantra Viewpoint - Building Moonshots : May-Jun 2024.pdf
Innomantra Viewpoint - Building Moonshots : May-Jun 2024.pdfInnomantra
 
#Mtp-Kit Prices » Qatar. Doha (+27737758557) Abortion Pills For Sale In Doha,...
#Mtp-Kit Prices » Qatar. Doha (+27737758557) Abortion Pills For Sale In Doha,...#Mtp-Kit Prices » Qatar. Doha (+27737758557) Abortion Pills For Sale In Doha,...
#Mtp-Kit Prices » Qatar. Doha (+27737758557) Abortion Pills For Sale In Doha,...drm1699
 
Jual Obat Aborsi Di Sibolga wa 0851/7541/5434 Cytotec Misoprostol 200mcg Pfizer
Jual Obat Aborsi Di Sibolga wa 0851/7541/5434 Cytotec Misoprostol 200mcg PfizerJual Obat Aborsi Di Sibolga wa 0851/7541/5434 Cytotec Misoprostol 200mcg Pfizer
Jual Obat Aborsi Di Sibolga wa 0851/7541/5434 Cytotec Misoprostol 200mcg PfizerPusat Herbal Resmi BPOM
 
Unlocking Growth The Power of Outsourcing for CPA Firms
Unlocking Growth The Power of Outsourcing for CPA FirmsUnlocking Growth The Power of Outsourcing for CPA Firms
Unlocking Growth The Power of Outsourcing for CPA FirmsYourLegal Accounting
 
Creating an Income Statement with Forecasts: A Simple Guide and Free Excel Te...
Creating an Income Statement with Forecasts: A Simple Guide and Free Excel Te...Creating an Income Statement with Forecasts: A Simple Guide and Free Excel Te...
Creating an Income Statement with Forecasts: A Simple Guide and Free Excel Te...Aurelien Domont, MBA
 
Presentation4 (2) survey responses clearly labelled
Presentation4 (2) survey responses clearly labelledPresentation4 (2) survey responses clearly labelled
Presentation4 (2) survey responses clearly labelledCaitlinCummins3
 
stock price prediction using machine learning
stock price prediction using machine learningstock price prediction using machine learning
stock price prediction using machine learninggauravwankar27
 
The Art of Decision-Making: Navigating Complexity and Uncertainty
The Art of Decision-Making: Navigating Complexity and UncertaintyThe Art of Decision-Making: Navigating Complexity and Uncertainty
The Art of Decision-Making: Navigating Complexity and Uncertaintycapivisgroup
 
Pitch Deck Teardown: Goodcarbon's $5.5m Seed deck
Pitch Deck Teardown: Goodcarbon's $5.5m Seed deckPitch Deck Teardown: Goodcarbon's $5.5m Seed deck
Pitch Deck Teardown: Goodcarbon's $5.5m Seed deckHajeJanKamps
 
High Profile Bangalore Just VIP Brigade Road 100% Genuine at your Door Step
High Profile Bangalore Just VIP Brigade Road 100% Genuine at your Door StepHigh Profile Bangalore Just VIP Brigade Road 100% Genuine at your Door Step
High Profile Bangalore Just VIP Brigade Road 100% Genuine at your Door Stepdarmandersingh4580
 
Top^Clinic ^%[+27785538335__Safe*Women's clinic//Abortion Pills In Harare
Top^Clinic ^%[+27785538335__Safe*Women's clinic//Abortion Pills In HarareTop^Clinic ^%[+27785538335__Safe*Women's clinic//Abortion Pills In Harare
Top^Clinic ^%[+27785538335__Safe*Women's clinic//Abortion Pills In Hararedoctorjoe1984
 
hyundai capital 2023 consolidated financial statements
hyundai capital 2023 consolidated financial statementshyundai capital 2023 consolidated financial statements
hyundai capital 2023 consolidated financial statementsirhcs
 
Toyota Kata Coaching for Agile Teams & Transformations
Toyota Kata Coaching for Agile Teams & TransformationsToyota Kata Coaching for Agile Teams & Transformations
Toyota Kata Coaching for Agile Teams & TransformationsStefan Wolpers
 
How to refresh to be fit for the future world
How to refresh to be fit for the future worldHow to refresh to be fit for the future world
How to refresh to be fit for the future worldChris Skinner
 
Abortion pills in Muscut<Oman(+27737758557) Cytotec available.inn Kuwait City.
Abortion pills in Muscut<Oman(+27737758557) Cytotec available.inn Kuwait City.Abortion pills in Muscut<Oman(+27737758557) Cytotec available.inn Kuwait City.
Abortion pills in Muscut<Oman(+27737758557) Cytotec available.inn Kuwait City.daisycvs
 
First Time Home Buyer's Guide - KM Realty Group LLC
First Time Home Buyer's Guide - KM Realty Group LLCFirst Time Home Buyer's Guide - KM Realty Group LLC
First Time Home Buyer's Guide - KM Realty Group LLCTammy Jackson
 
Understanding Financial Accounting 3rd Canadian Edition by Christopher D. Bur...
Understanding Financial Accounting 3rd Canadian Edition by Christopher D. Bur...Understanding Financial Accounting 3rd Canadian Edition by Christopher D. Bur...
Understanding Financial Accounting 3rd Canadian Edition by Christopher D. Bur...ssuserf63bd7
 
如何办理(SUT毕业证书)斯威本科技大学毕业证成绩单本科硕士学位证留信学历认证
如何办理(SUT毕业证书)斯威本科技大学毕业证成绩单本科硕士学位证留信学历认证如何办理(SUT毕业证书)斯威本科技大学毕业证成绩单本科硕士学位证留信学历认证
如何办理(SUT毕业证书)斯威本科技大学毕业证成绩单本科硕士学位证留信学历认证ogawka
 

Recently uploaded (20)

Shots fired Budget Presentation.pdf12312
Shots fired Budget Presentation.pdf12312Shots fired Budget Presentation.pdf12312
Shots fired Budget Presentation.pdf12312
 
Future of Trade 2024 - Decoupled and Reconfigured - Snapshot Report
Future of Trade 2024 - Decoupled and Reconfigured - Snapshot ReportFuture of Trade 2024 - Decoupled and Reconfigured - Snapshot Report
Future of Trade 2024 - Decoupled and Reconfigured - Snapshot Report
 
Innomantra Viewpoint - Building Moonshots : May-Jun 2024.pdf
Innomantra Viewpoint - Building Moonshots : May-Jun 2024.pdfInnomantra Viewpoint - Building Moonshots : May-Jun 2024.pdf
Innomantra Viewpoint - Building Moonshots : May-Jun 2024.pdf
 
#Mtp-Kit Prices » Qatar. Doha (+27737758557) Abortion Pills For Sale In Doha,...
#Mtp-Kit Prices » Qatar. Doha (+27737758557) Abortion Pills For Sale In Doha,...#Mtp-Kit Prices » Qatar. Doha (+27737758557) Abortion Pills For Sale In Doha,...
#Mtp-Kit Prices » Qatar. Doha (+27737758557) Abortion Pills For Sale In Doha,...
 
Jual Obat Aborsi Di Sibolga wa 0851/7541/5434 Cytotec Misoprostol 200mcg Pfizer
Jual Obat Aborsi Di Sibolga wa 0851/7541/5434 Cytotec Misoprostol 200mcg PfizerJual Obat Aborsi Di Sibolga wa 0851/7541/5434 Cytotec Misoprostol 200mcg Pfizer
Jual Obat Aborsi Di Sibolga wa 0851/7541/5434 Cytotec Misoprostol 200mcg Pfizer
 
Unlocking Growth The Power of Outsourcing for CPA Firms
Unlocking Growth The Power of Outsourcing for CPA FirmsUnlocking Growth The Power of Outsourcing for CPA Firms
Unlocking Growth The Power of Outsourcing for CPA Firms
 
Creating an Income Statement with Forecasts: A Simple Guide and Free Excel Te...
Creating an Income Statement with Forecasts: A Simple Guide and Free Excel Te...Creating an Income Statement with Forecasts: A Simple Guide and Free Excel Te...
Creating an Income Statement with Forecasts: A Simple Guide and Free Excel Te...
 
Presentation4 (2) survey responses clearly labelled
Presentation4 (2) survey responses clearly labelledPresentation4 (2) survey responses clearly labelled
Presentation4 (2) survey responses clearly labelled
 
stock price prediction using machine learning
stock price prediction using machine learningstock price prediction using machine learning
stock price prediction using machine learning
 
The Art of Decision-Making: Navigating Complexity and Uncertainty
The Art of Decision-Making: Navigating Complexity and UncertaintyThe Art of Decision-Making: Navigating Complexity and Uncertainty
The Art of Decision-Making: Navigating Complexity and Uncertainty
 
Pitch Deck Teardown: Goodcarbon's $5.5m Seed deck
Pitch Deck Teardown: Goodcarbon's $5.5m Seed deckPitch Deck Teardown: Goodcarbon's $5.5m Seed deck
Pitch Deck Teardown: Goodcarbon's $5.5m Seed deck
 
High Profile Bangalore Just VIP Brigade Road 100% Genuine at your Door Step
High Profile Bangalore Just VIP Brigade Road 100% Genuine at your Door StepHigh Profile Bangalore Just VIP Brigade Road 100% Genuine at your Door Step
High Profile Bangalore Just VIP Brigade Road 100% Genuine at your Door Step
 
Top^Clinic ^%[+27785538335__Safe*Women's clinic//Abortion Pills In Harare
Top^Clinic ^%[+27785538335__Safe*Women's clinic//Abortion Pills In HarareTop^Clinic ^%[+27785538335__Safe*Women's clinic//Abortion Pills In Harare
Top^Clinic ^%[+27785538335__Safe*Women's clinic//Abortion Pills In Harare
 
hyundai capital 2023 consolidated financial statements
hyundai capital 2023 consolidated financial statementshyundai capital 2023 consolidated financial statements
hyundai capital 2023 consolidated financial statements
 
Toyota Kata Coaching for Agile Teams & Transformations
Toyota Kata Coaching for Agile Teams & TransformationsToyota Kata Coaching for Agile Teams & Transformations
Toyota Kata Coaching for Agile Teams & Transformations
 
How to refresh to be fit for the future world
How to refresh to be fit for the future worldHow to refresh to be fit for the future world
How to refresh to be fit for the future world
 
Abortion pills in Muscut<Oman(+27737758557) Cytotec available.inn Kuwait City.
Abortion pills in Muscut<Oman(+27737758557) Cytotec available.inn Kuwait City.Abortion pills in Muscut<Oman(+27737758557) Cytotec available.inn Kuwait City.
Abortion pills in Muscut<Oman(+27737758557) Cytotec available.inn Kuwait City.
 
First Time Home Buyer's Guide - KM Realty Group LLC
First Time Home Buyer's Guide - KM Realty Group LLCFirst Time Home Buyer's Guide - KM Realty Group LLC
First Time Home Buyer's Guide - KM Realty Group LLC
 
Understanding Financial Accounting 3rd Canadian Edition by Christopher D. Bur...
Understanding Financial Accounting 3rd Canadian Edition by Christopher D. Bur...Understanding Financial Accounting 3rd Canadian Edition by Christopher D. Bur...
Understanding Financial Accounting 3rd Canadian Edition by Christopher D. Bur...
 
如何办理(SUT毕业证书)斯威本科技大学毕业证成绩单本科硕士学位证留信学历认证
如何办理(SUT毕业证书)斯威本科技大学毕业证成绩单本科硕士学位证留信学历认证如何办理(SUT毕业证书)斯威本科技大学毕业证成绩单本科硕士学位证留信学历认证
如何办理(SUT毕业证书)斯威本科技大学毕业证成绩单本科硕士学位证留信学历认证
 

The Role of Four Lipid Components Of LNPs.pdf

  • 1. Biopharma PEG https://www.biochempeg.com The Role of Four Lipid Components Of LNPs Lipid nanoparticles (LNPs) play an important role in COVID-19 mRNA vaccines. In addition, many preclinical and clinical studies have shown that LNPs have great potential in the field of nucleic acid therapy. The structural and biological properties of LNPs are not solely attributable to a single lipid component, but rather a combination of various types of lipids. Therefore, we will focus on describing the role of different lipid components in LNP preparation. Lipid Components of LNPs Generally, LNP consists of four components: ionizable cationic lipids, phospholipids, cholesterol, and PEG lipids (Figure 1). Each component plays a key role in terms of LNP stability, transfection efficacy and safety. Figure 1. Components of LNPs
  • 2. Biopharma PEG https://www.biochempeg.com Ionizable Cationic Lipids Ionizable cationic lipids are key components in the LNP formulation, and their acid dissociation constants (pKa) determine the ionization and surface charge of LNP, further affecting its stability and toxicity. Conventional permanently charged cationic lipids previously used for nucleic acid delivery (e.g., DOTAP) readily interact with negatively charged serum proteins and aggregate in the bloodstream, which can lead to rapid clearance of LNP by mononuclear phagocytes, resulting in a short half-life in the bloodstream. In addition, the relatively high hemolytic activity of cationic lipids increases the risk of toxic side effects, such as hemoglobin release due to red cell membrane damage. To avoid these problems, ionizable cationic lipids with pKa values typically ranging from 6.0 to 7.0 have been developed. This ionizable lipid-based LNP (iLNP) ensures efficient encapsulation of nucleic acids under acidic conditions and reduces toxicity during recycling under physiological conditions. Entering endosomes/lysosomes (pH below surface pKa), LNP can be positively charged again to facilitate endosome escape and release mRNA into the cytoplasm. It was found that LNP with pKa values of 6.2-6.5 and 6.6-6.9 favored hepatic delivery of siRNA in vivo and intramuscular administration of mRNA vaccines, respectively. Structurally, synthetic lipids usually contain three parts: (i) cationic or ionizable head groups, (ii) linker groups, and (iii) hydrophobic tails. The chemical diversity of each part results in a number of structurally distinct ionizable lipids that can be produced by combinatorial chemistry. Depending on the number of amino heads, ionizable cationic lipids can be classified as either monoamino or polyamino lipids. DLin-MC3-DMA (MC3), SM-102, and ALC-0315 are the best known monoamino acid lipids. They are also the three FDA-approved ionizable cationic lipids for RNA delivery. Researchers usually focus on tuning the lipid tail structure to confer enhanced potency or specific functions by changing the number of tails, designing linear or branching structures, and introducing unsaturated or biodegradable bonds, e.g., the unsaturated tails in MC3 and ester bonds in L319 play important roles in facilitating endosomal escape of siRNAs and accelerating intracellular degradation of lipids. By providing larger head groups, polyamino-ionizable cationic lipids have greater variability than monoamino-ionizable cationic lipids, and a
  • 3. Biopharma PEG https://www.biochempeg.com number of multitude of lipids have been designed and studied, e.g., 306O i10, cKK-E12, C12-200, 5A2-SC8, TT3, FTT5. Figure 2. The ionizable lipids used Comirnaty® (ALC-0315) and Spikevax® (SM-102) and in Onpattro® (MC3). Source: reference [1] PEG-lipids Even though PEG-lipids constitute the smallest molar percentage of the lipid components in LNPs (typically ∼1.5 mol%), they have several effects on the properties of lipid nanoparticles.  1. The amount of PEG-lipids can influence particle size and zeta potential;  2. PEG-lipids can better contribute to particle stability by decreasing particle aggregation;  3. Certain PEG modifications extend the blood circulation time of nanoparticles by lowering clearance mediated by the kidneys and the mononuclear phagocyte system (MPS).  4. PEG-lipids can be used to conjugate particular ligands to the particle for targeted delivery. The short chained diacyl PEG-lipid PEG-carbamate-1,2-dimyristoyl-sn-glycerol (PEG-c-DMG) is introduced in the Onpattro® formulation, which is rapidly dissociated from the lipid membrane. When dissociated from their PEG, LNPs can interact with blood proteins, including ApoE proteins, for delivery to the hepatocytes. In this context, two short lipids-PEG (C14) were recently used in the Comirnaty® and Spikevax® COVID-19 vaccines: ALC-0159 (DTA-PEG2000, ditetradecylacetamide) and DMG-PEG2000, respectively.
  • 4. Biopharma PEG https://www.biochempeg.com Figure 3. The PEG-lipids used in Onpattro® (PEG-c-DMG) , Spikevax® (PEG-DMG) and Comirnaty® (ALC-0159). Source: reference [1] However, PEGylation also presents a "PEG dilemma" that hinders interaction with target cells and subsequent endosomal escape, resulting in reduced transfection efficiency. Accelerated blood clearance ("ABC phenomenon") is an unexpected immunogenic response observed in PEG conjugates that results in rapid clearance of PEGylated nanocarriers. The ABC phenomenon has been widely observed after repeated dosing and reduces the effectiveness of PEG conjugates and nanocarriers. Another unexpected immune response is the hypersensitivity reaction known as complement activation-related pseudoallergy (CARPA), which significantly reduces the safety of PEGylated nanocarriers and has been associated with reduced efficacy of PEGylated treatments in clinical trials. The CARPA phenomenon has been categorized as a non-IgE-mediated pseudoallergic reaction caused by activation of the complement system. Various parameters of the PEG–lipid chemical structure including PEG size and architecture, lipid structure including hydrocarbon chains, headgroup, lipid–PEG linkage, and PEG terminal groups, are significant determinants of the PEGylated LNPs safety and bioactivity.
  • 5. Biopharma PEG https://www.biochempeg.com Figure 3. Scheme of the PEG–lipid structure. Source: reference [3]  ▶ PEG length is a key structural factor influencing the immunologic safety profile. The effect is biphasic, with both long and short chain PEG conjugates being more likely to induce the ABC phenomenon.  ▶ Like PEG length, PEG density (i.e., the percentage of PEG in the LNP) also exhibits a biphasic effect. However, both lower and higher densities of PEG exhibit a reduced ABC phenomenon.  ▶ Differences in PEG structure may have an effect, with branched PEG lipid conjugates conferring a higher degree of invisibility to LNP compared to linear PEG.  ▶ The functional terminal groups attached to the chain of the PEG particles are another factor that affects their immunogenicity and clearance.  ▶ Parameters such as size and surface charge also affect immunogenicity. For example, PEGylated carriers containing negatively charged phospholipids are more capable of stimulating the immune system through complement activation than uncharged vesicles.  ▶ As with the PEG fraction, the structure and length of the hydrophobic chains of lipids can determine not only the degree of immunogenicity but also its efficacy.  ▶ PEGylated LNP produced using a specific lipid anchoring group (e.g., cholesterol as an anchoring group) has more sustained permeability and higher systemic bioavailability in circulation.  ▶ Lipid linkage is an important parameter in the design and performance of lipids, where ester bonds replace carbamate bonds for the formation of unstable vesicles.
  • 6. Biopharma PEG https://www.biochempeg.com A thorough understanding of the correlation between the structural parameters of PEG lipids and the immune-related adverse effects of PEGylated LNPs, as well as their biophysical and physiological background, is an essential requirement. With this knowledge, optimal drug formulations that reduce and eliminate adverse immune reactions and improve the safety and efficiency of PEGylated drugs can be prepared. Helper Lipids - Cholesterol The inclusion of cholesterol in nucleic acid-containing LNP formulations is based primarily on two major findings obtained with liposomal formulations of small molecule therapeutics: 1) cholesterol is an exchangeable molecule that can accumulate within liposomes during circulation, 2) cholesterol dramatically reduces the amount of surface-bound proteins and improves the circulating half-life. Therefore, equimolar amounts of cholesterol are included in LNP formulations relative to endogenous membranes; this prevents net efflux or influx and maintains membrane integrity. Lipids such as cholesterol are also essential for encapsulating nucleic acids. Since cholesterol increases membrane rigidity, it reduces drug leakage from the liposomal core. However, for large cargo such as nucleic acids, this effect may not be important. As the design of ionizable lipids has improved, providing more potency and less toxicity, the total proportion of helper lipid has decreased. However, a recent study noted that a certain threshold amount of helper lipids is still needed to promote stable encapsulation. Biopharma PEG can supply high-quality cholesterol (plant-derived) from lab to large scale to meet your research and drug development needs.
  • 7. Biopharma PEG https://www.biochempeg.com Figure 4. The molecular shape of standard helper lipids, including DSPC, DOPE, and cholesterol, used in LNPs. Source: reference [1] Helper Lipids – Phospholipids Phospholipids are helper lipids that contribute to the formation of lipid nanoparticles and the escape of endosomes. Commonly used phospholipids in preclinical studies and clinical applications are DSPC and DOPE. Phospholipids can spontaneously organize into lipid bilayers and the higher phase transition temperature enhances the membrane stability of LNPs. Similar to 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 (e.g., by adding fatty acid tails). DSPC is a structural lipid used in LNPs for siRNA therapy (Onpattro) and SARS-CoV-2 mRNA vaccines. DSPC consists of a phosphatidylcholine head group and two saturated 18-carbon tails, with the two tails forming a tightly packed lipid bilayer. In LNP, DSPC is mainly located on the surface of the nanoparticles and in more marginal positions in the core of the nanoparticles. DOPE is another phospholipid commonly used in preclinical studies of LNP. The unsaturated tails of DOPE not only form a more fluid lipid bilayer but also are capable of forming a hexagonal-phase (HII) organized form, which facilitates the fusion of lipid membranes with endosomal membranes, leading to cytoplasmic nucleic acid release.
  • 8. Biopharma PEG https://www.biochempeg.com Conclusion Under the premise of consistent preparation conditions, the nucleic acid composition and the proportion of lipids have a decisive influence on the structure of nanoparticles. Understanding the function of various types of lipids is a prerequisite for the optimization of LNP formulations, and the roles of four common components of LNPs are briefly described in the paper. Biopharma PEG is a dynamic science company dedicated to PEG derivatives. We are capable of supplying small to large quantities of a rich selection of PEG derivatives with GMP & non-GMP standards for your mRNA vaccine R&D. We can produce and provide classic PEG lipids, such as mPEG-DMG, ALC-0159 and mPEG-DSPE for your LNPs R&D. References: [1] Hald Albertsen C, Kulkarni JA, Witzigmann D, Lind M, Petersson K, Simonsen JB. The role of lipid components in lipid nanoparticles for vaccines and gene therapy. Adv Drug Deliv Rev. 2022 Sep;188:114416. doi: 10.1016/j.addr.2022.114416. Epub 2022 Jul 3. PMID: 35787388; PMCID: PMC9250827. [2] Hou, X., Zaks, T., Langer, R. et al. Lipid nanoparticles for mRNA delivery. Nat Rev Mater 6, 1078–1094 (2021). https://doi.org/10.1038/s41578-021-00358-0 [3] PEGylated Lipid Nanoparticle Formulations: Immunological Safety and Efficiency Perspective, Rumiana Tenchov, Janet M. Sasso, and Qiongqiong Angela Zhou, Bioconjugate Chemistry 2023 34 (6), 941-960, DOI: 10.1021/acs.bioconjchem.3c00174 Related Articles: Application of Lipid Nanoparticles In Vaccine And Drug Delivery Liposomes vs. Lipid Nanoparticles: Which Is Best for Drug Delivery? Lipid nanoparticles (LNPs) In Cancer Immunotherapy PEGylated Liposomes in the Clinic and Clinical Trials