Extracellular vesicles as emerging platforms for modulating innate immune responses in 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.