Lipid nanoemulsion incorporating DOTAP reverse micelles as clinically translatable carriers of ALDH inhibitors for lung cancer therapy

Lung cancer remains the most prevalent malignancy worldwide and the leading cause of cancer-related deaths. Bridging academic innovation and industrial applications is critical for developing scalable drug delivery systems for pulmonary therapies. In this study, we designed and optimized a lipid nanosystem incorporating the cationic lipid DOTAP by utilizing reverse micelle structures to enhance pulmonary tropism. Fluorescence quenching assays confirmed the incorporation of reverse micelles into the oily core, thus validating the structural integrity of the system. This nanosystem was tailored for the encapsulation of ABD0171, a potent inhibitor of ALDH1A3, an enzyme strongly associated with chemoresistance in lung cancer. Physicochemical characterization revealed robust colloidal properties with a particle size of 60 nm, surface charge of +45 mV, and encapsulation yield of 99%. In vitro , formulations with/without DOTAP demonstrated high efficacy against epithelial-like H358 cells derived from human bronchioalveolar carcinoma, with IC50 values < 5 µM. Chicken Chorioallantoic Membrane (CAM) evaluations demonstrated good tolerability of the DOTAP-containing formulation and significant H358 tumor reduction by 28% compared with the untreated control, while maintaining a favorable safety profile. By combining industrially feasible methods with FDA-approved components, this study demonstrated the potential of DOTAP-containing lipid nanosystems as scalable platforms for pulmonary drug delivery. These findings provide a pathway for future applications in cancer therapy, bridging the gap between nanosystem innovation and clinical translation.