Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep 10:385:114053.
doi: 10.1016/j.jconrel.2025.114053. Epub 2025 Jul 18.

Lung tissue-optimized gene editing in human cystic fibrosis models following topical application of lipid nanoparticles

Affiliations
Free article

Lung tissue-optimized gene editing in human cystic fibrosis models following topical application of lipid nanoparticles

Belal Tafech et al. J Control Release. .
Free article

Abstract

Cystic fibrosis (CF) is a severe monogenic disease characterized by debilitating lung dysfunction caused by loss-of-function mutations in the CFTR gene. While CRISPR-based gene editing holds promise for correcting these mutations and potentially curing CF, efficient delivery of gene editors to the lung epithelium through the mucosal barrier remains a major challenge. In this study, we developed a lung-optimized gene editing strategy using lipid nanoparticles (LNPs) and evaluated it in increasingly complex, biomimetic human-based and patient-derived models. Systematic optimization of helper lipids, genetic cargo, guide RNA modifications, and gene editor ratios, alongside analysis of innate immune responses, achieved ∼50 % editing efficiency in the model gene HPRT in two-dimensional models. Editing efficiency significantly dropped to ∼5 % in biomimetic three-dimensional CF bronchial epithelial tissue models following topical LNP application. Pretreatment with the approved mucolytic agent dornase alpha increased editing efficiency to ∼12.7 %. Finally, in CF patient-derived cells harboring the CFTRR1162X mutation, our optimized LNP formulation achieved ∼12 % correction on gene level, offering a potential treatment avenue for this yet untreatable mutation. Taken together, this study demonstrates that optimizing the genetic cargo as well as the delivery vehicle is key when striving for clinically applicable treatment approaches. It further provides insights into gene editing rates in human-based normal and CF patient-derived bronchial tissue models which express all relevant biological barriers and, thus, can pave the way for topically applicable treatment options for patients with CF and other genetic lung diseases.

Keywords: CFTR; Cystic fibrosis; Gene editing; Gene therapy; Lipid nanoparticles; Pulmonary gene delivery; Transmucosal delivery.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest PRC has a financial interest in Acuitas Therapeutics and NanoVation Therapeutics as well as being Chair of NanoVation Therapeutics. KA and JK are employees of NanoVation Tx and JK is a co-founder. MAM reports grants and contracts from the German Research Foundation (DFG), the German Federal Ministry of Education and Research (BMBF), Boehringer Ingelheim, Enterprise Therapeutics and Vertex Pharmaceuticals with payments made to the institution; personal fees for advisory board participation or consulting from Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotech, Splisense, Vertex Pharmaceuticals; lecture honoraria from Vertex Pharmaceuticals; and travel support from Boehringer Ingelheim and Vertex Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

MeSH terms

LinkOut - more resources