Lung organoids for respiratory diseases: overcoming translational hurdles in drug discovery and safety assessment

Respiratory diseases, encompassing chronic inflammatory conditions, interstitial fibrotic disorders, acute infectious diseases, and pulmonary malignancies, represent a profound global health burden with unacceptably high morbidity and mortality rates. Historically, the pharmaceutical pipeline for respiratory therapeutics has suffered staggering attrition rates during clinical development. This is primarily due to the fundamental inability of conventional two-dimensional cell cultures and in vivo animal models to faithfully recapitulate the complex three-dimensional architecture, multicellular heterogeneity, and human-specific physiological dynamics of the pulmonary system. To bridge this critical translational gap, lung organoids—self-organizing, three-dimensional microphysiological constructs derived from pluripotent or adult stem cells—have emerged as a useful human-cell-based platform. This comprehensive review critically evaluates current lung organoid technologies, elucidating their derivation pathways and capacity for high-fidelity disease modeling. We analyze their application in dissecting the pathogenesis of chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, viral infections including SARS-CoV-2, and non-small cell lung cancer. Furthermore, we highlight their important role in predictive toxicology for assessing environmental inhalation hazards, cosmetic safety, and drug-induced lung injury, aligning with evolving regulations prioritizing alternatives to animal testing. Despite their immense potential, widespread clinical and industrial translation is currently impeded by biological bottlenecks: the absence of functional vascularization, incomplete immune integration, and reliance on undefined xenogeneic matrices. We systematically examine bioengineering strategies addressing these limitations—including synthetic hydrogels, microfluidic organ-on-a-chip platforms, and 3D bioprinting—to overcome translational hurdles, accelerate precision medicine, and improve respiratory pharmacology.