Antioxidant lipid nanoparticles enhance mRNA stability for regeneration therapy and gene editing

The success of mRNA vaccines has motivated the development of mRNA therapeutics to treat a wide range of diseases, as well as applications in regenerative medicine. However, the inherent instability of mRNA under conditions of oxidative stress renders these applications challenging. Here we report a general approach to shield mRNA from oxidative degradation by incorporating antioxidant lipid within lipid nanoparticles (LNPs). Specifically, we design a library of antioxidant ionizable lipids and identify a lead LNP formulation containing a 4-hydroxyphenyl-modified antioxidant lipid. Mechanistically, we show that antioxidant LNPs directly scavenge reactive species and preserve mRNA integrity under extracellular and intracellular oxidative stress. Across multiple organ and tissue injury models, we demonstrate that AO12LNPs sustain high-level and durable protein expression and restore higher transcript integrity than conventional clinically used LNPs, leading to improved regenerative outcomes and more efficient genome editing. Our findings highlight the potential of AOLNPs as a next-generation mRNA delivery platform, capable of overcoming challenging oxidative conditions in regenerative medicine. Here the authors develop an antioxidant lipid nanoparticle to protect mRNA from oxidative damage, enabling stronger, longer-lasting protein expression and improving regenerative therapies and genome editing across different disease models.