Toward Precision Electrochemical Sensing of CFTR Function in Cystic Fibrosis Models

: The assessment of cystic fibrosis transmembrane conductance regulator (CFTR) activity is essential to both diagnose and evaluate the efficacy of treatments in cystic fibrosis (CF). In particular, the prompt evaluation of genotype-specific responses to CFTR modulators might lead to more precise therapeutic approaches. In this study, a flexible electrochemical sensor modified with silver nanoparticles was developed and applied for the electrochemical quantification of chloride ions in CF epithelial cell models. The sensing platform exhibited a linear analytical response toward chloride in both aqueous solutions and chloride-free buffer, with limits of detection in the submillimolar range, enabling the discrimination of chloride concentrations under various conditions. Chloride ions were detected in apical surface liquids obtained from epithelial cultures carrying different CFTR pathogenic variants: the effect of the elexacaftor/tezacaftor/ivacaftor (ETI) treatment, as a CFTR modulator, was differentiated from untreated samples. Chloride concentrations were determined by differential pulse voltammetry using the standard addition method, and results were further normalized to express chloride secretion considering the final apical fluid volume. ETI treatment induced genotype-dependent increases in chloride secretion, with the largest functional recovery observed in responsive genotypes such as F508del/F508del and L1077P/L1077P. A strong correlation was found between chloride levels and normalized secretion rates, confirming how direct electrochemical measurements reliably reflect CFTR functional changes. Overall, this work demonstrates that portable sensors provide a rapid, cost-effective, and scalable approach for functional CFTR evaluation, supporting their potential application in the personalized assessment of CFTR modulator efficacy, namely theratyping.