Enhanced Delivery of Oral Biomacromolecules through Edible Plant-Derived Nanovehicles: Exploiting the Self-Amplifying Trancytosis Feedback Loop and Phosphatidic Acid

The intestinal epithelium poses a formidable obstacle to the systemic absorption of the oral nanovehicles. Despite the development of extracellular vesicles (EVs) for drug delivery, there has been limited exploration into edible-product-derived EVs (EP-EVs), particularly those derived from plants as carriers to enhance the oral delivery of biomacromolecules. Here, we evaluated the potential of EP-EVs and highlighted their promising application and underlying mechanisms as orally delivered carriers from plant-derived EVs. Grape-derived EVs (Gra-EVs) were found to have superior efficacy in oral delivery of insulin to T1D rats compared to ginger-derived EVs (Gin-EVs) and milk-derived EVs (Mi-EVs), attributed to their enhanced endocytosis, secretion pathways, and more efficient transcytosis across epithelia. The capacity of Gra-EVs to regulate epithelial proteins associated with cytoskeletal organization, secretion, and recycling-related transport facilitated a robust positive feedback loop known as the self-amplifying feedback loop, thereby enhancing intestinal absorption. Notably, phosphatidic acid (PA), the phospholipid abundant in plant-derived EVs, was proved to augment the transcytosis through MAPK/ERK1/2 signaling pathway activation. Thus, edible plant-derived EVs, especially Gra-EVs, exploited the self-amplifying feedback loop and phosphatidic acid for improved oral delivery of biomacromolecules.