Inhalation of Mesenchymal-Stem-Cell-Derived Nanovesicles Delivering Catalase Enhances the Treatment for Acute Lung Injury

Acute lung injury (ALI) is characterized by the excessive accumulation of reactive oxygen species (ROS), which triggers a severe inflammatory cascade and the destruction of the alveolar-capillary barrier, leading to respiratory failure and life-threatening outcomes. Considering the limitations and adverse effects associated with current therapeutic interventions, developing effective and safe strategies that target the complex pathophysiological mechanisms of ALI is crucial for improving patient outcomes. Herein, we developed an inhalable, multifunctional nanotherapeutic (MSCNVs@CAT) by encapsulating catalase (CAT) in mesenchymal-stem-cell-derived nanovesicles (MSCNVs). Specifically, CAT scavenged ROS by efficiently decomposing H2O2 into water and oxygen, exhibiting potent antioxidant properties. Meanwhile, MSCNVs contained inherent mesenchymal-stem-cell-derived factors, including transforming growth factor-β, interleukin-10, hepatocyte growth factor, and so on, which proved immunomodulatory and regenerative capabilities in clinical studies. Inhalation of MSCNVs@CAT facilitated targeted pulmonary delivery and elicited potent therapeutic effects by the synergistic interplay of antioxidant, anti-inflammatory, and reparative functions. Consequently, MSCNVs@CAT restored inflammatory homeostasis in ALI by balancing the pro-inflammatory/anti-inflammatory immune responses and repairing the alveolar-capillary barriers. The mechanisms are primarily associated with the NF-κB and cell-cell junction signaling pathways. Overall, this study presented potent inhalable nanotherapeutics for treating ALI, which possessed significant translational potential for the effective and safe treatment of pneumonia.