Smart nebulized ROS-responsive hydrogel microspheres loaded with UC-MSCs-derived exosomes for the treatment of acute lung injury.

Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) are rapidly progressing, highly fatal clinical syndromes characterized by acute and progressive hypoxic respiratory failure. These conditions result in significant morbidity and mortality, yet no specific treatments are currently available, with management relying largely on symptomatic and supportive care. The pathogenesis of ALI/ARDS is closely linked to the excessive production of reactive oxygen species (ROS) and an uncontrolled inflammatory response, which collectively drive disease progression and tissue damage. To address this, we have developed a novel ROS-responsive hydrogel microsphere encapsulating human umbilical mesenchymal stem cell-derived exosomes, designated Exo@TK@CaAlg hydrogel microspheres. The design incorporates thioketal bonds, endowing the microspheres with both effective ROS-scavenging ability and specific responsiveness to oxidative stress. Exo@TK@CaAlg microspheres exhibit a small particle size and excellent biocompatibility in vitro and in vivo. Their potent ROS scavenging capacity positions them as a promising therapeutic approach for alleviating ALI. In preclinical studies, these microspheres have been successfully delivered via nebulization to the lungs of ALI mice, where they play a critical role in mitigating oxidative stress and inflammation. The treatment enhances pulmonary capillary barrier integrity, reduces protein exudation, restores mitochondrial function, and promotes the transition of macrophages from a pro-inflammatory to an anti-inflammatory phenotype. These collective findings highlight the potential of Exo@TK@CaAlg hydrogel microspheres as a therapeutic strategy for ALI/ARDS.