Emerging role of plant-derived extracellular vesicles in human health and disease.

Plant-derived extracellular vesicles (PDEVs) are emerging plant-derived vesicle preparations that have attracted considerable interest as potential natural nanocarriers for therapeutic delivery owing to their ability to transport bioactive lipids, proteins, nucleic acids, and plant-derived metabolites. Increasing evidence suggests that specific PDEV preparations can modulate intercellular communication, influence immune responses, and facilitate the delivery of bioactive cargo in specific preclinical models. Recent studies have demonstrated their potential applications in inflammatory bowel disease, cancer, liver disorders, metabolic diseases, and tissue repair. However, the biological properties and therapeutic performance of PDEVs vary considerably depending on plant species, tissue origin, processing and isolation methods, vesicle composition, dosage, and experimental models. Furthermore, important challenges, including nomenclature, biogenesis, vesicle heterogeneity, distinction between naturally secreted vesicles and processing-derived nanoparticles, standardized isolation and characterization, biodistribution, and quality control, remain unresolved. The proposed mechanisms of cross-kingdom RNA communication and tissue-specific targeting also require further experimental validation before clinical translation. In particular, cross-kingdom RNA transfer remains controversial because of concerns regarding RNA contamination, physiological abundance, RNA stability, cellular uptake, and direct target validation. This review critically summarizes current knowledge on PDEV biogenesis, molecular composition, isolation and characterization strategies, cellular uptake, biodistribution, and therapeutic applications. In addition, it discusses recent advances, unresolved controversies, and translational challenges, including large-scale manufacturing, batch-to-batch reproducibility, pharmacokinetic evaluation, safety assessment, regulatory considerations, and standardization requirements. By integrating recent findings and identifying existing knowledge gaps, this review provides an updated perspective on the opportunities and limitations of PDEVs as emerging nanotherapeutic platforms for future biomedical applications.