Chronic lung diseases arise from complex interactions between environmental exposures and host genetic factors. However, these interactions are not fully understood, and despite decades of study, effective curative therapies remain unavailable for many patients. Recent breakthroughs in therapeutic gene-editing have become a reality for some inherited blood diseases and are a promising approach for monogenic lung diseases. Early-phase clinical studies are now ongoing for AATD, primarily through liver-directed editing of hepatocytes to restore circulating functional AAT and for COVID-19 using gene-edited immune cell approaches. However, direct in vivo gene-editing of pulmonary epithelial cells remains largely at the preclinical stage. Expanding this therapeutic pipeline requires overcoming the unique biological barriers of the lung and developing human-specific models that faithfully recapitulate human disease mechanisms. Advances in gene-editing technologies, including CRISPR-Cas9 systems, base and prime editors, and emerging compact nucleases, have increased the feasibility of precise genomic correction. However, safe and efficient delivery directly to the lung remains a major unmet challenge due to mucus, surfactant, epithelial tight junctions, and innate immune surveillance. Delivery systems such as engineered AAVs, lentiviral vectors, selective organ targeting lipid nanoparticles and aerosolizable formulations like nebulised or dry powder nanoparticles are beginning to address these obstacles. In parallel, human preclinical models have evolved from traditional cell lines to more sophisticated platforms such as iPSC-derived airway and alveolar cells, organoids, precision-cut lung slices, air-liquid interface cultures, organ-on-a-chip devices, and patient-derived primary cells. These models enable mechanistic interrogation, variant-specific functional assessment, and preclinical evaluation of gene-editing strategies with increased physiological relevance. In this review, we detail current and emerging gene-editing tools, delivery strategies, and human-relevant disease models. We highlight key translational barriers and discuss how advanced human models combined with improved delivery technologies can accelerate the development of safe and effective gene-editing therapeutics for chronic respiratory disease.
