E20 is a charge-switching ionizable lipid developed for efficient nucleic acid delivery with reduced inflammatory toxicity. Its carboxylic acid–tertiary amine headgroup changes charge between acidic formulation conditions and physiological pH, while two hydroxylated spacers and branched 8×6 hydrophobic tails support nucleic acid encapsulation and cytosolic delivery. E20 nanoparticles generated approximately 600 mU/mL serum hEPO after intravenous mRNA administration in mice. Unlike multiple benchmark LNPs, E20 did not exacerbate cytokine production in LPS-pretreated mice or human PBMCs. E20 also enabled sustained pDNA expression without the acute lethality observed with MC3-LNPs and improved IL-22 mRNA treatment in a mouse model of acute lung injury. E20 remains a preclinical research lipid.
