Microphysiological system-based respiratory toxicity assessment: recent advances and regulatory perspectives.

UNLABELLED: The respiratory tract is continuously exposed to airborne chemicals, particles, and pathogens, underscoring the growing need for predictive, human-relevant approaches to inhalation toxicity and pulmonary safety assessment. Conventional animal models and static in vitro cultures frequently fall short because of species differences and their inability to reproduce key lung microenvironmental cues, such as the air-liquid interface (ALI), vascular perfusion, and breathing-like mechanical strain. Microphysiological systems (MPS), including lung- and airway-on-a-chip platforms, help address these limitations by integrating multicellular co-culture, controlled transport, and biomimetic mechanical stimulation to emulate airway and alveolar physiology. This review summarizes recent engineering advances in respiratory MPS, including platform architectures, membranes and extracellular matrix, cell sources, and biomimetic inputs. Furthermore, we discuss fit-for-purpose endpoint selection and exposure modalities for drug safety assessment and environmental and industrial chemical toxicology. We highlight emerging directions, including immune-competent models, quantitative dosimetry for ALI aerosol exposure, and multi-organ coupling, which may further improve the mechanistic and translational value of respiratory MPS. Finally, we outline current regulatory signals and industrial adoption trends, and emphasize the need for standardized performance metrics, integrated quality control frameworks, and clearly defined contexts of use to support broader qualification and regulatory confidence in respiratory MPS data. Collectively, respiratory MPS are gaining importance as promising human-relevant approaches for more mechanistically informative and translationally relevant respiratory toxicity assessment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s43188-026-00372-w.