Cell-specific exosomes in sepsis-associated ARDS: from immunometabolic reprogramming to precision medicine

The publication of the 2023 Global Definition of ARDS has further unveiled the clinical heterogeneity of sepsis-induced acute respiratory distress syndrome (ARDS), rendering traditional systemic biomarkers insufficient for precisely characterizing lung-specific pathological changes. Cell-specific exosomes, owing to their high stability and high fidelity to the molecular signatures of their parent cells, have emerged as a highly promising tool for liquid biopsy. This review aims to elucidate how exosomes construct a multidimensional communication network within the compromised alveolar-capillary barrier. Beyond exploring the traditional function of exosomes as inflammatory vectors, we provide an in-depth analysis of the mechanisms by which alveolar epithelial exosomes propagate ferroptosis and mitochondrial damage in a wave-like manner, and how macrophage exosomes drive immunometabolic reprogramming via glycolysis and histone lactylation to sustain the inflammatory state. Furthermore, we elaborate on the central role of endothelial exosomes in vascular leakage and immunothrombosis, proposing a novel hypothesis that they may serve as mediators propagating cuproptosis within the vascular bed. Finally, by integrating advances in single-cell omics and analyzing technical barriers such as isolation specificity and timeliness, we propose a precision medicine framework based on exosomal molecular fingerprints. This strategy aims to utilize exosomes for ARDS subphenotyping, thereby promoting a paradigm shift in clinical practice from syndrome management to mechanism-driven theranostics.