In this study, the extraction process of grape pomace from the Lebanese autochthonous cultivar Asswad Karech was enhanced through the selection of specific parameters, yielding an antioxidant extract (20 mg/mL) that was co-loaded with resveratrol (5 mg/mL) into phospholipid vesicles containing penetration enhancers (PEVs). Propylene glycol (PG) was incorporated as a penetration enhancer at concentrations of 10, 20, and 30% to obtain 10PG-PEVs, 20PG-PEVs, and 30PG-PEVs. Vesicle preparation was achieved through direct sonication, yielding unilamellar and bilamellar vesicles with an average size of ∼205
234 nm, a monodisperse distribution (polydispersity index <
0.3), and a negative surface charge (∼-54
-56 mV). The formulations containing 30% propylene glycol exhibited long-term stability, maintaining a consistent mean diameter over 12 months at room temperature (25 °C). Upon nebulization using the Next Generation Impactor, the vesicular dispersions successfully reached the deepest stages of the impactor, mimicking deposition in the lower respiratory airways. Biocompatibility studies on A549 and CuFi-1 cell lines demonstrated that the vesicles co-loaded with grape extract and resveratrol effectively counteracted apoptosis induced by hydrogen peroxide. Furthermore, when 16HBE bronchial epithelial cells were exposed to cigarette smoke extract, vesicles containing 30% propylene glycol inhibited reactive oxygen species (ROS) generation. These findings highlight the potential of phospholipid vesicles co-loaded with grape pomace extract and resveratrol, particularly those formulated with 30% propylene glycol, for pulmonary administration to mitigate oxidative damage associated with cigarette smoke exposure and related respiratory diseases.