Review of preclinical EVs for sepsis-associated acute lung injury

Sepsis-associated acute lung injury (ALI) remains a major challenge in intensive care units, characterized by dysregulated innate immune responses that drive both excessive inflammation and subsequent immunosuppression. In recent years, extracellular vesicles (EVs) and EV-inspired biomimetic nanosystems have attracted increasing attention as candidate platforms for modulating immune imbalance in ALI. This review summarizes recent advances in understanding the immunopathological mechanisms underlying sepsis-associated ALI, including macrophage polarization imbalance, excessive neutrophil extracellular trap (NET) formation, dendritic cell functional exhaustion, and dysregulation of key signaling pathways such as TLR4, NLRP3 inflammasome, and cGAS–STING. We further discuss how naturally derived EVs and engineered EV-mimetic carriers may influence these pathogenic processes through the delivery of bioactive cargoes, drawing primarily from preclinical observations. In addition, current strategies for pulmonary-targeted delivery, EV engineering approaches, and major translational considerations, including biosafety, manufacturing standardization, and quality control, are critically evaluated. Although most available evidence derives from preclinical studies, EV-based biomimetic nanosystems represent a promising research direction that may complement existing anti-inflammatory strategies by integrating immune modulation, inflammation control, and tissue repair. Continued mechanistic investigation and clinically relevant validation will be essential for determining their therapeutic feasibility in sepsis-associated ALI.