Nanocarrier potential of small cardamom-derived exosome-like nanovesicles for the delivery of appetite-enhancing peptide, Ghrelin

Human appetite is tightly regulated by Ghrelin (GHRL), a 28aa peptide hormone. In an empty stomach, GHRL is
secreted by the stomach epithelial glandular cells which acts on the hypothalamus, leading to appetite stimu­
lation and food intake. Loss of appetite, known as anorexia is a debilitating problem in patients undergoing
chemotherapy as well as soldiers working at high altitudes (HA), primarily caused by lower plasma GHRL.
Though restoration of plasma GHRL may re-establish appetite, naked GHRL delivery via enteral route is not
possible due to its degradation in the gastrointestinal (GI) tract while parenteral route administration is
discouraged due to its low plasma half-life. Plant-derived nanovesicles (PDNVs) are exosome-mimetic vesicles
naturally present in plants. PDNVs are emerging as natural nanocarriers for the delivery of distinct cargoes for
both in vitro and in vivo applications. Cardamom seeds are a nutraceutical spice with known appetite-stimulating
attributes. Herein, we encapsulated GHRL peptide in small cardamom-derived PDNVs (SCDNVs) by active
sonication and evaluated its in vitro bioavailability and gastrointestinal stability. SCDNVs exhibited high
encapsulation efficiency for GHRL and were non-toxic to Caco-2 cells. Compared to native GHRL, SCDNV-
encapsulated GHRL displayed better intracellular delivery potential in Caco2 cells and was resistance to the
simulated gastrointestinal digestion process in vitro. Further, SCDNVs also possessed appetite-stimulating phy­
tochemicals such as α-terpinyl acetate and α-terpinol. Hence, GHRL-encapsulated SCDNVs represent a synergistic
cocktail of an appetite-inducing hormone and phytochemicals in bioavailable form for anorexia therapy.