bioRxiv : the preprint server for biologyNov 24, 2025

Using gene editing and nanoparticles to change airway cells needed for cystic fibrosis treatment

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 3, 2026

Abstract

A common disease-causing splice site variant was corrected in primary cystic fibrosis airway cells using base editor RNAs.

Single-cell RNA sequencing showed a significant increase in detectable CFTR transcript levels in most CF airway epithelial cell types.
There was notable enrichment of CFTR-expressing ionocytes and secretory goblet cells following the correction.
Edited progenitor basal cell subtypes decreased as a fraction of total cells compared to unedited cells.
CRISPR base editors delivered by polymeric nanoparticles successfully restored CFTR function to clinically meaningful levels in both immortalized and primary airway cells.
Polymeric nanoparticles were able to deliver reporter encoding RNA to progenitor airway cells in fully differentiated cultures.
Vitronectin was identified as a major component of the nanoparticle corona formed in vivo, although pre-incubation with vitronectin did not enhance delivery.

Simplified

Cystic Fibrosis (CF) is a life-limiting genetic disorder caused by deleterious variants in thegene that results in altered mucous impairing the airway epithelia. Durable correction of these variants in airway cells remain a therapeutic challenge for ~10% of individuals unresponsive to CFTR modulators. A common disease-causingsplice site variant was corrected in primary CF airway cells using base editor RNAs. Single-cell RNA sequencing revealed a remarkable increase in detectabletranscript in most CF airway epithelial cell types with notable enrichment of-expressing ionocytes and secretory goblet cells. Progenitor basal cell subtypes were edited but they decreased as a fraction of total cells andexpressing cells compared to unedited cells. CRISPR base editors delivered by polymeric nanoparticles (PNPs) facilitated functional rescue of CFTR to clinically meaningful levels in immortalized and primary airway cells. PNPs delivered reporter encoding RNA to progenitor airway cells in fully differentiated airway cultures. Vitronectin was a major component of the PNP corona that formed in vivo, but pre-incubation with vitronectin did not enhance delivery. Together, these findings validate a scalable, non-viral platform with significant translational promise for treating CF and other respiratory diseases involving respiratory epithelial cell dysfunction. CFTR CFTR CFTR CFTR CFTR

Full Text

Full text is available at the source.

View Full Text ↗

Funding

Competing interests

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jordan Green reports financial support was provided by National Institutes of Health. Garry Cutting reports financial support was provided by Cystic Fibrosis Foundation. Stephany Tzeng reports financial support was provided by National Institutes of Health. Jordan Green reports a relationship with Dome Therapeutics that includes: board membership, consulting or advisory, and equity or stocks. Jordan Green reports a relationship with Cove Therapeutics that includes: board membership, consulting or advisory, and equity or stocks. Jordan Green reports a relationship with WyveRNA Therapeutics that includes: board membership and equity or stocks. Jordan Green reports a relationship with VasoRx that includes: board membership and equity or stocks. Garry Cutting reports a relationship with Cystic Fibrosis Foundation that includes consulting or advisory. Gregory Newby reports that he has filed patents on base editing technology. Johns Hopkins University has filed a patent application based on technology discussed in this manuscript with J.J.G., S⋅Y.T., G.R.C., and E.W.K. as co-inventors. The other authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

PubMed

Using gene editing and nanoparticles to change airway cells needed for cystic fibrosis treatment

Abstract

Full Text

Funding

Competing interests

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the crispr gene editing brief

Abstract

Full Text

Funding

Competing interests

Related papers

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the crispr gene editing brief