Grapefruit-derived EVs, alongside those from C. paradisi, exhibited strong cytotoxicity against tumor cells, especially A375 melanoma cells, resulting in substantial viability reduction, cell cycle arrest, the downregulation of phosphorylated ERK and AKT, and a decrease in key mediators (ICAM1 and cathepsin) associated with cancer progression. Here, ICAM1 is linked to melanoma.