Extracellular vesicles derived from Citrus plants: innovative applications in therapeutics and drug delivery

Citrus-derived extracellular vesicles (Citrus-EVs) have attracted increasing interest as naturally occurring nanovesicles that possess intrinsic bioactivity and hold promise for drug delivery applications. Sourced from edible Citrus plants, these vesicles exhibit a lipid bilayer structure enriched with plant-specific proteins, nucleic acids, lipids, and secondary metabolites, which confer high biocompatibility, low immunogenicity, and favorable stability in physiological environments. This review summarizes recent progress in the isolation, purification, and characterization of Citrus-EVs, highlighting methodological approaches and current technical limitations. We also outline their demonstrated biological functions, including antitumor, anti-inflammatory, immunomodulatory, antioxidant, and gut microbiota-modulating activities, and discuss their emerging utility as versatile drug carrier platforms. In addition, we evaluate major strategies for cargo loading and delivery, along with representative applications in the therapeutic administration of small-molecule drugs, nucleic acids, and proteins. Finally, key challenges related to standardization, mechanistic insight, and clinical translation are presented, together with prospects for future research. Overall, this review aims to clarify the current landscape and translational potential of Citrus-EVs as natural nanodelivery systems for therapeutic applications.