DLin-M-C3-DMA (Dilinoleylmethyl-4-dimethylaminobutyrate; MC3) is an ionizable cationic lipid featuring a central tertiary amine headgroup (dimethylaminobutyrate) esterified to a dilinoleylmethanol backbone. The molecule incorporates two polyunsaturated C18:2 (linoleyl) alkyl chains, each containing two cis double bonds (9Z,12Z), which contribute to its cone‑shaped geometry and pH‑dependent membrane destabilizing activity. The C3 spacer between the dimethylamino group and the ester carbonyl provides optimal charge distribution and endosomal escape kinetics. With an apparent pKa of 6.44, DLin-M-C3-DMA is neutrally charged at physiological pH but becomes positively charged in the acidic endosomal environment, enabling efficient siRNA and mRNA encapsulation, cellular uptake, and cytosolic release. DLin-M-C3-DMA is widely regarded as the gold standard ionizable lipid for siRNA delivery and has been clinically validated in Onpattro® (patisiran), the first FDA‑approved siRNA therapeutic for hereditary transthyretin‑mediated amyloidosis.
DLin-M-C3-DMA (MC3) is an ionizable cationic lipid that has been used in the generation of lipid nanoparticles (LNPs) encapsulating siRNA, mRNA, or plasmid DNA for use in vitro and in vivo. As a potent siRNA delivery vehicle, DLin-M-C3-DMA facilitates the electrostatic complexation of negatively charged nucleic acids and promotes endosomal escape due to its pH‑dependent charge switching behavior. Clinically, DLin-M-C3-DMA has been employed in LNPs encapsulating transthyretin‑directed siRNA for the treatment of hereditary transthyretin‑mediated amyloidosis‑induced polyneuropathy (Onpattro®). The two polyunsaturated linoleyl tails in DLin-M-C3-DMA contribute to its low toxicity profile and efficient gene silencing activity, with an ED₅₀ of 0.005 mg/kg achieved in murine Factor VII models. For these reasons, DLin-M-C3-DMA remains the benchmark ionizable lipid against which novel LNP formulations are compared.
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FAQ
Q1: What is DLin-M-C3-DMA?
A: DLin-M-C3-DMA (MC3) is an ionizable cationic lipid that serves as a potent siRNA delivery vehicle in lipid nanoparticles (LNPs). It is the key ionizable lipid in Onpattro® (patisiran), the first FDA‑approved siRNA therapeutic.
Q2: Is DLin-M-C3-DMA soluble in aqueous buffers?
A: DLin-M-C3-DMA is insoluble in water. It is soluble in organic solvents including ethanol, DMSO, DMF, and chloroform. For LNP formulation, lipids are dissolved in ethanol before mixing with aqueous nucleic acid solutions.
Application Scenarios
1. siRNA Therapeutic Development
DLin-M-C3-DMA is the clinically validated ionizable lipid for siRNA delivery, used in Onpattro® (patisiran) for hereditary transthyretin‑mediated amyloidosis. It is the benchmark lipid for hepatic gene silencing applications.
2. mRNA Vaccine Manufacturing
MC3‑based LNPs have been employed in preclinical and clinical studies for mRNA vaccine delivery, including COVID‑19, influenza, and personalized cancer vaccines.
3. CRISPR‑Cas9 Gene Editing Delivery
DLin-M-C3-DMA is used in LNPs for the delivery of CRISPR‑Cas9 mRNA and guide RNA for therapeutic gene editing in preclinical models of genetic disorders.
4. LNP Formulation Optimization
Pharmaceutical scientists use MC3 as a benchmark ionizable lipid to optimize LNP manufacturing parameters, compare novel lipid candidates, and develop high‑potency nucleic acid delivery systems.
5. Analytical Method Development for LNPs
Reference grade DLin-M-C3-DMA serves as a standard for developing and validating HPLC, LC‑MS, and other analytical methods for quantifying ionizable lipid content in LNP drug products.
6. Quality Control Release Testing
Essential reference standard for QC release testing of MC3‑based LNP drug products, including identity, purity, and content uniformity assays.
7. In Vitro and In Vivo Gene Silencing Studies
Used in cell culture and animal model studies to evaluate siRNA‑mediated gene silencing potency, with established ED₅₀ values (0.005 mg/kg in murine FVII model) serving as benchmarks for novel LNP formulations.
Contact Us
Looking for the gold standard ionizable lipid for your siRNA or mRNA delivery program? Cosperpharm supplies high‑purity DLin-M-C3-DMA with comprehensive documentation to support your research and regulatory submissions. Contact our team to request a quote, discuss custom packaging, or arrange a technical consultation.
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