Nature nanotechnologySep 9, 2026

Ionizable lipids that change charge reduce the toxicity of lipid nanoparticles

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Sep 10, 2026

Abstract

Switchable nanoparticles, made from ionizable lipids, do not activate key inflammatory pathways.

Ionizable lipids can switch their charge depending on pH levels, enhancing their effectiveness as nucleic acid delivery systems.
These nanoparticles encapsulate nucleic acids and promote their release from cells without triggering inflammation.
They show improved treatment outcomes in models of acute lung injury compared to traditional lipid nanoparticles.
The reduced activation of inflammatory signaling pathways may contribute to their lower toxicity profile.

Simplified

Lipid nanoparticles (LNPs) have great potential as nucleic acid delivery vehicles; however, they trigger the production of inflammatory cytokines, which limits their medical applications. Developing non-inflammatory LNPs is challenging because the LNP's ionizable lipid and the process of endosomal disruption are the major sources of LNP toxicity but are also essential for delivering nucleic acids. Here we demonstrate that ionizable lipids containing a carboxylic acid and an amine (termed S-lipid) switch their charged state between the pHs of 7.4 and 4.0, allowing them to generate LNPs (termed switchable nanoparticles) that efficiently encapsulate nucleic acid and trigger endosomal release without activation of the TLR4, complement, galectin-8 and platelet activating factor signalling pathways. Finally, we demonstrate that switchable nanoparticles are better at treating lipopolysaccharide-induced acute lung injury than traditional LNPs because they do not exacerbate pre-existing inflammation. Collectively, these results demonstrate that negatively charged ionizable lipids can mitigate the toxicity of LNPs.