Enhanced Uptake and Retention of an Acidic Sophorolipid Delivery System Boosts Acute Lung Injury Therapy.

Acute lung injury (ALI), characterized by dysregulated inflammation, remains a life-threatening condition with high clinical morbidity and mortality. Aerosol inhalation offers a promising route for targeted pneumonia therapy; however, its efficacy is significantly limited by poor drug penetration through the airway mucus barrier. To address this challenge, we developed an innovative surfactant-based delivery system utilizing ring-opened sophorolipids (acidic sophorolipids, aSL), which endowed them with both surfactant properties and amphiphilicity, thereby achieving dual functionalities: (1) facilitating enhanced cellular endocytosis and prolonged pulmonary retention and (2) serving as a versatile platform for hydrophobic drug encapsulation. All-trans retinoic acid (ATRA), as a representative hydrophobic drug, was assembled into sophorolipids, forming aSL@ATRA, which effectively mitigated lung tissue damage by downregulating inflammatory cell infiltration (including macrophages, neutrophils, and monocytes) and key proinflammatory cytokine secretion, while preserving the alveolar-capillary barrier integrity. Moreover, aSL@ATRA exhibited a favorable safety profile, with nearly no observable adverse effects in ALI-bearing mice. These findings position aSL@ATRA as a breakthrough noninvasive inhalation platform, offering substantial therapeutic potential not only for ALI but also for other refractory respiratory diseases.