Journal of pharmaceutical sciencesApr 24, 2026

A charge-changing lipid that makes stable, low-inflammation mRNA nanoparticles without using PEG

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 28, 2026

Abstract

Essence

A new charge-reversible lipid enabled PEG-free mRNA nanoparticles that stayed dispersed, triggered less inflammation, and slightly increased protein expression in vivo.

Evidence

This preclinical formulation study synthesized the phospholipid-like lipid DOP-TMDEDA and compared its PEG-free and PEGylated LNPs with commercially available ionizable-lipid LNPs for dispersibility, in vivo inflammatory cytokine induction, and protein expression.

Caveat

Because this is a delivery-platform study based on preclinical dispersibility, cytokine, and expression readouts, it does not establish clinical safety or therapeutic benefit in humans.

Simplified

The development of lipid nanoparticles (LNPs) facilitated optimal usage of mRNA drugs to achieve clinical success during the COVID-19 pandemic. Conventional LNPs rely on ionizable lipids for mRNA encapsulation and endosomal escape. However, the high hydrophobicity of ionizable lipids leads to aggregation of these LNPs under physiological conditions, requiring polyethylene glycol (PEG) modification for stabilization. Ionizable lipids and PEG induce inflammation and hypersensitivity reactions, respectively, after intramuscular administration. Therefore, developing low-inflammatory LNPs is essential for safer application of mRNA therapeutics. In this study, we synthesized 2-{[2-(dimethylamino)ethyl]methylamino}ethyl 1,2-dioleoyl-1,2-dioleoyl-sn-glycero-3-phosphate (DOP-TMDEDA), a novel charge-reversible lipid structurally similar to natural glycerophospholipids. In contrast with LNPs prepared using commercially available ionizable lipids, which exhibit poor dispersibility without PEG modification in phosphate-buffered saline, DOP-TMDEDA-based LNPs (TM LNPs) formed uniformly without PEG modification and showed high dispersibility. PEG-free TM LNPs [TM LNPs PEG (-)] induced markedly lower inflammatory cytokine production in vivo than LNPs prepared with commercially available lipids. Furthermore, TM LNPs PEG (-) showed a slightly higher level of protein expression in vivo than PEGylated TM LNPs. Collectively, these results indicate that TM LNPs PEG (-) provide a promising and biocompatible mRNA delivery platform for mRNA therapeutics.