Extracellular Vesicle-Mediated Macrophage Polarization in Sepsis-Induced Acute Lung Injury: Molecular Mechanisms and Therapeutic Opportunities.

Sepsis-induced acute lung injury (SI-ALI) is a severe complication of sepsis characterized by dysregulated inflammatory responses and impaired immune homeostasis. Growing evidence indicates that extracellular vesicles (EVs), particularly exosomes, are important mediators of intercellular communication. Despite the heterogeneity of infectious sources underlying sepsis, EVs can regulate macrophage polarization and functional reprogramming by transferring diverse bioactive cargo. Consequently, EVs are involved in the pathophysiological progression of SI-ALI arising from sepsis of different etiologies. However, the mechanisms through which distinct EV cargos regulate macrophage function and contribute to SI-ALI pathogenesis remain incompletely understood. To address these issues, this review summarizes how different EV subtypes and their cargos, including RNAs, proteins, lipids, and DNA, modulate macrophage functional states through multiple signaling pathways. The effect of such processes further contributes to inflammatory reaction, immune balance, and tissue regeneration in acute lung injury caused by damage to the SI-ALI. Particularly, the EV-mediated modulation of macrophage function goes beyond the rigid M1/M2 dichotomy, being rather based on the dynamic functional repertoire involving both pro-inflammatory response and immune regulation as well as tissue regeneration. The article finally concludes with EV-based treatment approaches aimed at cargo delivery or blocking and the main problems related to translational medicine. Overall, the review article identifies the macrophage regulatory network controlled by EVs, thus helping to understand immunopathogenesis of SI-ALI as well as laying the theoretical foundation for developing EV-based precision medicine.