Researchers at the University of Pennsylvania's Perelman School of Medicine have developed a groundbreaking method for safely delivering therapeutic DNA to cells using lipid nanoparticles (LNPs), potentially transforming treatment approaches for millions of patients with chronic diseases including heart disease, diabetes, and cancer.
The innovative technique, recently published in Nature Biotechnology, successfully overcomes decades-long safety barriers that previously prevented effective DNA delivery to cells. This advancement could represent the next frontier in genetic medicine following the mRNA revolution that led to COVID-19 vaccines.
Overcoming a 20-Year Challenge in Genetic Medicine
"For 20 years, DNA delivery with LNPs has been a major goal in this field," explained Jake Brenner, MD, PhD, assistant professor of Medicine and Pharmacology at Penn. "We're picking up where mRNA left off to tackle bigger challenges."
The research builds directly on the genetic medicine revolution pioneered at Penn by Nobel Prize winners Katalin Kariko, PhD, and Drew Weissman, MD, PhD, who developed the technology for safe mRNA delivery that became fundamental to COVID-19 vaccines.
While mRNA therapies have advanced rapidly in recent years, they face significant limitations for treating chronic conditions. mRNA breaks down quickly in the body—typically within hours—and cannot easily target specific cell types. DNA delivery offers a compelling alternative, as DNA remains active in cells for months or even years and can be programmed to function only in targeted cells.
However, previous attempts to use LNPs for DNA delivery triggered severe immune reactions. When loaded into standard mRNA-LNPs, DNA proved lethal to 100% of healthy mice in laboratory tests, creating what seemed to be an insurmountable safety barrier.
The STING Pathway and Safety Solution
Brenner's team identified the root cause of these dangerous reactions: DNA-carrying LNPs activated the body's STING (stimulator of interferon genes) pathway—a defensive mechanism that normally helps fight infections but causes harmful inflammation when inappropriately triggered.
The researchers initially explored nucleotide modifications similar to those used by Kariko and Weissman to make mRNA delivery safe. When this approach proved ineffective for DNA delivery, they discovered a critical alternative: nitro-oleic acid (NOA), a natural anti-inflammatory molecule produced by cells.
By incorporating NOA into the DNA-carrying particles, the team completely eliminated the fatal reactions that had previously made this approach impossible. In laboratory tests, all mice receiving the improved DNA delivery system survived.
Advantages Over Existing Gene Therapy Approaches
The new DNA-LNP system offers several significant advantages over both mRNA therapies and viral vector-based gene therapies:
- Extended Duration: Treated cells produced therapeutic proteins for approximately six months from a single dose—dramatically longer than the few hours typical of mRNA therapies
- Larger Payload Capacity: The system can carry larger genetic instructions compared to viral methods
- Reduced Immune Reactions: The approach causes fewer immune reactions than viral vectors
- Precise Targeting: DNA-LNPs can target specific cells more precisely
- Repeat Administration: Unlike viral vectors, the treatment can be given multiple times without losing effectiveness
"This technology holds incredible promise—not just to treat diseases, but to fundamentally change how we address health challenges that affect millions," Brenner stated. "It builds directly on Penn's pioneering work in mRNA and represents the next generation of precision medicine."
Future Directions
The research team is now focused on further refining the technology and testing its effectiveness in different tissues and disease models. The potential applications span numerous chronic conditions that affect millions of patients worldwide.
The research was funded in part by the American Heart Association (24PRE1195406) and the National Institute for Health (R01-HL-153510, R01-HL160694, R01-HL164594, and R21-AI153064).
The study, titled "Safer non-viral DNA delivery using lipid nanoparticles loaded with endogenous anti-inflammatory lipids," was published in Nature Biotechnology (doi: 10.1038/s41587-025-02556-5).
