UCLA Researchers Demonstrate Non-Viral Full-Length CFTR Gene Insertion Using Lipid Nanoparticles

Researchers at University of California, Los Angeles have developed a lipid nanoparticle (LNP)-based gene-editing strategy capable of inserting a full-length, functional CFTR gene into human airway cells — marking a potential breakthrough in mutation-agnostic gene therapy for cystic fibrosis (CF).

The study, published in Advanced Functional Materials, demonstrates that LNPs can be engineered to deliver all components required for precise genomic insertion of a large gene without the use of viral vectors.

Led by Dr. Steven Jonas of the UCLA Broad Stem Cell Research Center, the team designed LNPs to simultaneously deliver:

• CRISPR gene-editing machinery

• Guide RNAs targeting a precise genomic locus

• A DNA repair template containing a full-length CFTR gene

The CFTR gene, mutations of which cause cystic fibrosis, is particularly challenging due to its size and the existence of more than 1,700 disease-causing variants.

In laboratory-grown human airway cells carrying a severe CF mutation, the system achieved successful gene insertion in approximately 3–4% of cells. Notably, this modest correction rate restored between 88% and 100% of normal CFTR channel function across the cell population.

The strong functional recovery was attributed in part to codon optimization strategies developed in collaboration with Dr. Donald Kohn’s lab at UCLA, enhancing CFTR protein expression without altering protein structure.

Unlike mRNA-based approaches that require repeated dosing, this strategy integrates the corrected gene into the genome, offering the potential for durable, long-term therapeutic benefit. However, efficient targeting of airway stem cells — which regenerate lung epithelium — remains a key translational hurdle.

The researchers describe the work as proof of concept, highlighting the broader potential of modular, non-viral LNP platforms for delivering large genes in genetic lung diseases and beyond.