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

  • Nat Biotechnol. 2025 Feb 5. doi: 10.1038/s41587-025-02556-5.
Manthan N Patel  #  1  2 ,  Sachchidanand Tiwari  #  2  3 ,  Yufei Wang  2 ,  Sarah O'Neill  1  2 ,  Jichuan Wu  2 ,  Serena Omo-Lamai  2  4 ,  Carolann Espy  1  2 ,  Liam S Chase  2  4 ,  Aparajeeta Majumder  2 ,  Evan Hoffman  2 ,  Anit Shah  2 ,  András Sárközy  3 ,  Jeremy Katzen  2 ,  Norbert Pardi  3 ,  Jacob S Brenner  5  6
Affiliations
  • 1. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 2. Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PA, USA.
  • 3. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 4. Department of Bioengineering, School of Engineering & Applied Science, University of Pennsylvania, Philadelphia, PA, USA.
  • 5. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. [email protected].
  • 6. Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PA, USA. [email protected].
  • # Contributed equally.
PMID: 39910195 DOI: 10.1038/s41587-025-02556-5
Abstract

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 (NOA-pDNA-LNPs) ameliorated serious inflammatory responses in vivo, enabling safer, prolonged transgene expression-11.5 times greater than that of mRNA-LNPs at day 32. Additionally, we performed a small LNP formulation screen to iteratively optimize transgene expression and increase expression 50-fold in vitro. pDNA-LNPs loaded with NOA and Other bioactive molecules should advance genetic medicine by enabling longer-term and promoter-controlled transgene expression.

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