Modeling the lung‒brain axis in critical illness: Multifactorial crosstalk through organoids and organ‐on‐a‐chip system

Abstract Neurological sequelae, ranging from acute brain dysfunction (e.g., delirium) to long‐term cognitive impairment, are increasingly recognized as significant complications in survivors of critical care units, particularly in patients with lung injury caused by severe pulmonary inflammation mechanical ventilation. However, the underlying mechanisms linking lung injury to neurological dysfunction remain poorly understood. Traditional in vitro and animal models face significant limitations in replicating complex, bidirectional interactions between lungs and the brain. This review narratively summarizes the current understanding of how severe pulmonary infections contribute to brain dysfunction, focusing on key pathophysiological pathways such as systemic inflammation, infection‐associated hypoxia, mechanical ventilation‐induced injury, and alterations in the pulmonary microenvironment. We highlight recent advances in the development and application of lung and brain organoids, as well as multiorgan‐on‐a‐chip technologies, which enable modeling of complex inter‐organ crosstalk that traditional models cannot capture. Furthermore, we discuss how these cutting‐edge platforms can simulate clinically relevant processes—such as ventilator‐associated pneumonia, acute respiratory distress syndrome, and infection‐induced cognitive impairment‐offering promising avenues for preclinical mechanistic studies and informing future therapeutic development and patient stratification in critical illness. By critically analyzing the current limitations of organoid and organ‐on‐a‐chip systems, we propose future directions to enhance their mechanistic fidelity, standardization, and translational potential. This comprehensive approach ultimately improve our understanding of lung‒brain interactions targeting multiorgan dysfunction in intensive care setting.