RESEARCHERS at University California, Los Angeles (UCLA) have developed a lipid nanoparticle (LNP)-based system capable of delivering the full cystic fibrosis transmembrane conductance regulator (CFTR) gene into human airway cells. The LNPs carry CRISPR/Cas9 components, guide RNAs, and a linear DNA template for homology-directed repair, allowing precise insertion of the complete CFTR gene without the use of viral vectors. This non-viral approach overcomes limitations associated with traditional viral delivery, including payload size, immune reactions, and restrictions on repeated administration.
Restoring Function in Severe Mutations
Cystic fibrosis is caused by mutations in the CFTR gene, which encodes a chloride channel critical for maintaining airway fluid balance. About 10% of patients produce minimal or no CFTR protein, making them unresponsive to existing CFTR modulator drugs. In lab-grown airway cells carrying a severe G542X mutation, the LNP system successfully delivered a functional CFTR gene into 3–4% of cells. Despite this modest integration, the approach restored 88–100% of chloride channel function across the cell population, aided by codon optimisation that enhances protein production without altering the CFTR protein itself.
Potential for Durable, One-Time Treatment in Cystic Fibrosis
Unlike mRNA therapies requiring repeated dosing, this strategy inserts the corrected gene directly into the genome, offering the potential for long-term expression. Targeting long-lived airway stem cells remains a key challenge, as these cells are located deep within the lung lining and are protected by the thick mucus characteristic of cystic fibrosis. Reaching and editing these cells would provide a continual source of healthy airway epithelium throughout a patient’s life.
A Platform with Broad Implications
Because the LNP system is modular and does not rely on viral vectors, it could be adapted to other genetic lung disorders caused by large genes with multiple mutations. This platform provides a scalable, potentially more affordable alternative to conventional gene therapy, offering the possibility of mutation-agnostic treatment for patients currently lacking effective options.
Takeaways
This study demonstrates proof of concept for a non-viral, full-gene insertion method capable of restoring functional CFTR channels in human airway cells. While challenges remain in delivering therapy to airway stem cells, the research lays the groundwork for mutation-independent gene therapies for cystic fibrosis and other inherited lung disease
References
Tiare Dunlap, UCLA Health. Nanoparticle-based gene editing could expand treatment options for cystic fibrosis. 2026. Available at: https://www.uclahealth.org/news/article/nanoparticle-based-gene-editing-could-expand-treatment. Last accessed: 18 February 2026.
Foley RA et al. Lipid nanoparticles for the delivery of CRISPR/Cas9 machinery to enable site-specific integration of CFTR and mutation-agnostic disease rescue. Adv Funct Mater. 2026; DOI:10.1002/adfm.202502540.
