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.