Unroasted and Roasted Coffee-Derived Extracellular Vesicles Inhibit Proliferation and Migration of SK-MEL-28 Melanoma Cells via Distinct Molecular Pathways

Abstract

Abstract Melanoma is among the most common cancers in both men and women, and it can spread earlier and more aggressively than other skin cancers, driving demand for innovative and biocompatible therapeutic strategies. Coffee, one of the most widely consumed beverages worldwide, has been epidemiologically linked to a reduced risk of several cancers, including melanoma. It contains bioactive compounds with reported anti-cancer properties; however, the molecular mechanisms underlying its potential protective effects against melanoma remain insufficiently explored. Plant-derived extracellular vesicles (EVs) have emerged as promising natural nanocarriers due to their high stability, cellular uptake efficiency, and low toxicity. Here, we report the first comparative investigation of EVs isolated from unroasted and roasted Coffea arabica beans and their anti-cancer effects on SK-MEL-28 melanoma cells. Both EV types selectively reduced SK-MEL-28 cell viability, induced apoptosis, suppressed tumor spheroid growth, and impaired cellular migration. Mechanistically, unroasted coffee EVs downregulated SERPINA1 and inhibited the PI3K/AKT pathway, whereas roasted coffee EVs attenuated MAPK signaling by reducing BRAF phosphorylation. These findings demonstrate that coffee-derived EVs exhibit potent anti-melanoma activities through distinct oncogenic pathways and identify them as edible, naturally occurring nanocarriers with therapeutic potential against skin cancer.