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  • Michael Nguyen

What are Ionizable Lipids?

Introduction to Ionizable Lipids


Ionizable lipids, or ionizable cationic lipids, are a class of engineered lipids that can change their charge state depending on the acidity (pH) of their environment. Unlike permanently charged cationic lipids, ionizable lipids are neutral at physiological pH, which enhances their compatibility with the human body and reduces toxicity. This ability to adjust charge dynamically is particularly useful in the safe and effective delivery of nucleic acids like mRNA and siRNA.


How Ionizable Lipids Work


  • At Physiological pH: Ionizable lipids remain neutrally charged, which helps LNPs circulate in the bloodstream without excessive immune detection or clearance.

  • At Acidic pH: Once LNPs reach the acidic environments of target cell endosomes, the ionizable lipids become positively charged. This charge shift promotes the release of the lipid nanoparticle’s payload into the cell cytoplasm by disrupting the endosomal membrane, a process essential for successful delivery.


Key Benefits of Ionizable Lipids


1. Enhanced Delivery Efficiency: Ionizable lipids facilitate the efficient encapsulation and delivery of genetic material into cells.


2. Reduced Cytotoxicity: Because they are neutral at body pH, ionizable lipids are less toxic compared to their permanently charged counterparts, making them safer for use in humans.


3. Improved Stability and Circulation Time: Neutral charges at physiological pH reduce interactions with blood components, thus enhancing the circulation time of these lipid-based carriers.


Some notable examples of ionizable lipids are: DLin-MC3-DMA, SM-102, ALC-0315, LP-01, DODAP, DODMA, and much more.





Fig. 1 - Example of an ionizable cationic lipid: SM-102 readily available for use.


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