Researchers at the University of California Los Angeles (UCLA) have developed a lipid nanoparticle-based gene-editing method that can insert a full healthy gene into human airway cells. This technology has restored key biological function in laboratory models of cystic fibrosis and may offer a new direction for treating inherited lung diseases regardless of the specific mutation involved.
The study, published in Advanced Functional Materials, demonstrates that lipid nanoparticles—commonly used to deliver mRNA vaccines—can be engineered to transport the necessary components for precise insertion of a large gene into the genome without relying on viral vectors.
“This work shows that we can package everything needed for precise gene insertion into a single, non-viral delivery system,” said Dr. Steven Jonas, senior author and member of the UCLA Broad Stem Cell Research Center. “That’s a critical step toward developing gene therapies that can work across many different disease-causing mutations.”
Cystic fibrosis is caused by mutations in the CFTR gene, which encodes a channel responsible for moving chloride and water across airway cell surfaces. Malfunction of this channel leads to thick mucus in the lungs, trapping bacteria and causing chronic infections and progressive damage. While current drugs known as CFTR modulators help many patients, about 10% produce little or no CFTR protein and do not benefit from these treatments.
“For those patients, gene therapy isn’t just an improvement — it’s really the only option,” said Dr. Brigitte Gomperts, co-author and associate director of translational research at UCLA’s stem cell center. “You have to give the cell the ability to make the protein in the first place.”
Given over 1,700 different CFTR mutations that can cause cystic fibrosis, researchers sought a universal approach rather than targeting each mutation individually. Traditional methods use viral vectors to deliver genetic material but face challenges such as limited cargo capacity and immune response risks.
Instead, UCLA researchers used lipid nanoparticles to carry three elements: CRISPR machinery for DNA cutting, guide molecules for targeting specific genome sites, and a DNA template with a full copy of the CFTR gene.
“Getting all of that into a single particle — especially a gene as large as CFTR — is something that hadn’t been shown before,” said Ruth Foley, first author and recent Ph.D. graduate from Jonas’s lab at UCLA. “If you can solve the ‘big gene’ problem, it opens the door for a lot of other diseases as well.”
Testing on lab-grown human airway cells with severe cystic fibrosis mutations showed that about 3–4% received the healthy CFTR gene through nanoparticles. Despite this small percentage, normal CFTR channel function was restored in 88–100% of treated cells.
The effectiveness is attributed to how researchers designed the replacement CFTR gene for maximum protein production after entering cells—a process called codon optimization developed by collaborators in Dr. Donald Kohn’s lab at UCLA.
Unlike strategies delivering messenger RNA—which require repeated dosing—the new method inserts corrected genes directly into genomes so cells and their descendants could potentially keep producing functional CFTR over time.
“These stem cells are long-lived and constantly regenerate the airway,” said Gomperts, who is also professor at David Geffen School of Medicine at UCLA. “If you can correct them, you could, in theory, have a lasting source of healthy cells.”
However, reaching airway stem cells remains challenging due to natural barriers within lungs and additional mucus buildup in cystic fibrosis patients.
“This paper is a proof of concept,” said Jonas. “It shows that we can package and deliver the right genetic cargo. The next challenge is getting it to the right cells in the body.”
Because lipid nanoparticles are modular and non-viral, this platform may offer more flexibility and scalability than traditional approaches while being easier to adapt or re-dose if needed.
“This kind of platform gives you room to iterate,” Foley said. “If you need to re-dose or adapt the cargo for a different disease, you’re not starting from scratch.”
Researchers believe this strategy could apply beyond cystic fibrosis—to other genetic lung diseases or conditions involving large genes with multiple mutations.
“For patients who currently have no effective treatments,” Gomperts said, “this kind of work represents hope — not because it will be ready tomorrow, but because it shows a path forward.”
Additional authors include Paul G. Ayoub, Vrishti Sinha, Colin Juett, Alicia Sanoyca, Emily C. Duggan, Lindsay E. Lathrop, Priyanka Bhatt, Kevin Coote and Beate Illek.
This research was supported by several organizations including the National Institutes of Health and the Cystic Fibrosis Foundation.
UCLA has achieved national recognition through accomplishments such as Nobel laureates and MacArthur Fellows (https://www.ucla.edu/). The university operates within the University of California system (https://www.ucla.edu/) and maintains excellence across scholarship fields (https://www.ucla.edu/), fostering diverse perspectives on its 419-acre campus (https://www.ucla.edu/).