Safer non-viral DNA delivery using lipid nanoparticles loaded with endogenous anti-inflammatory lipids

The value of lipid nanoparticles (LNPs) for delivery of messenger RNA (mRNA) was demonstrated by the coronavirus disease 2019 (COVID-19) mRNA vaccines, but the ability to use LNPs to deliver plasmid DNA (pDNA) would provide additional advantages, such as longer-term expression and availability of promoter sequences. However, pDNA-LNPs face substantial challenges, such as toxicity and low delivery efficiency. Here we show that pDNA-LNPs induce acute inflammation in naive mice that is primarily driven by the cGAS-STING pathway. Inspired by DNA viruses that inhibit this pathway for replication, we loaded endogenous lipids that inhibit STING into pDNA-LNPs. Loading nitro-oleic acid (NOA) into pDNA-LNPs…

• AH
  American Heart Association

  Award: 24PRE1195406
• NH
  National Heart, Lung, and Blood Institute

  Awards: R01-HL164594, R01-HL-153510, R01-HL160694
• NI
  National Institute of Allergy and Infectious Diseases

  Award: R01AI153064