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Poster: 256Selective mRNA delivery to airway epithelial cells by a novel polymer-lipid-based PEp-SENS™ platform for cystic fibrosis
Abstract   Peer reviewed

Poster: 256Selective mRNA delivery to airway epithelial cells by a novel polymer-lipid-based PEp-SENS™ platform for cystic fibrosis

J. Han, K. Yum, S. Yoo, J. Park, W. Shahin, K. Campbell, Y. Tang, K. Kim, R. Vamsee, S. Lee, …
Journal of cystic fibrosis, Vol.25(Suppl 2), pp.130-131
09/2026
DOI: 10.1016/j.jcf.2026.07.287

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Abstract

Although CFTR modulators have improved outcomes for many people with cystic fibrosis (CF), a subset of patients have mutations that are unresponsive to these therapies or cannot tolerate them, highlighting the need for mutation-agnostic approaches. Inhaled CFTR mRNA therapy could address this unmet need, but efficient pulmonary delivery remains challenging because nanoparticles must tolerate aerosolization, penetrate airway mucus, and ransfect airway epithelial cells. Therapeutic success further depends on sufficient epithelial expression to restore CFTR function in diseased airways. To address these barriers, we developed a biodegradable polymer-lipid-based Selectivity Enabling NanoShell (SENS™) platform, termed PEp-SENS, for airway delivery and epithelial uptake. We therefore evaluated the aerosol compatibility, pulmonary delivery, and airway epithelial tropism and functional potential of PEp-SENS-delivered CFTR mRNA in mouse and transgenic ferret lungs, including a CF-relevant ferret model. Nebulizer compatibility was assessed by physicochemical properties, aerosol performance, and RNA integrity. Pulmonary delivery and cellular biodistribution were evaluated in BALB/c mice and ROSA26mT/mG transgenic ferrets after intratracheal administration of aerosolized PEp-SENS-mRNA formulations using immunofluorescence-based cell type characterization and flow cytometry. To assess delivery under CF-like mucus barrier conditions, PEp-SENS-Cre mRNA was also evaluated in CFTRG551D/G551D ROSA-TG ferrets. Functional activity of ferret CFTR mRNA-loaded PEp-SENS was evaluated in CF ferret ALI cultures in vitro and in a CF ferret model in vivo. PEp-SENS-mRNA maintained colloidal properties and RNA integrity following aerosolization, demonstrated nebulizer compatibility, and generated respirable aerosols, with more than 70% of droplets within the lung-deposition size range. In mice, intratracheally delivered PEp-SENS-mRNA achieved robust pulmonary reporter expression with preferential delivery to airway epithelial cells. In transgenic ferrets, PEp-SENS-mRNA efficiently transfected conducting airway epithelial cells and rare submucosal gland cells. In the trachea and proximal conducting airways, transfected cells were mainly FOXJ1-positive ciliated cells, with occasional MUC5AC-positive goblet cells, while both ciliated and SCGB1A1-positive club cells were identified in smaller airways. In CFTRG551D/G551D ROSA-TG ferrets, PEp-SENS-mediated mRNA delivery remained efficient despite thick viscous mucus, and transfection was observed in submucosal gland tubules, including myoepithelial cells. Functional efficacy studies using ferret CFTR mRNA-loaded PEp-SENS in CF ferret ALI cultures and CF ferrets are in progress. PEp-SENS is an inhalable mRNA delivery platform that enables efficient in vivo transfection of airway epithelial cells while maintaining formulation stability during aerosolization. Its ability to generate respirable aerosols and mediate airway epithelial and submucosal gland transfection in a CF ferret model supports further investigation of PEp-SENS as a pulmonary RNA delivery platform for cystic fibrosis. Ongoing functional efficacy studies are the first to utilize ferret CFTR mRNA and will enable testing of repeat in vivo dosing without compounding immunogenicity.

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