2. Academic Validation
  3. Safer non-viral DNA delivery using lipid nanoparticles loaded with endogenous anti-inflammatory lipids

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

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. jacob.brenner@pennmedicine.upenn.edu.
  • 6 Division of Pulmonary, Allergy, and Critical Care, Department of Medicine, Perelman School of Medicine, University of Pennsylvania Philadelphia, Philadelphia, PA, USA. jacob.brenner@pennmedicine.upenn.edu.
  • # 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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