Past, Present, and Future of Plant-Derived Extracellular Vesicles in Biomedical Applications.

Plant-derived extracellular vesicles (PDEVs) have emerged as promising natural nanocarriers for biomedical applications owing to their distinctive ability to facilitate intercellular communication and transport bioactive molecules. In this review, we employ bibliometric analysis to identify research hotspots and trends, providing a comprehensive overview of these core themes. The bibliometric results reveal a sustained increase in annual publications in this field, with keyword analysis identifying drug delivery, cross-kingdom regulation, immunomodulation, engineering modification, and gut microbiota as five major research themes. The focus of research has evolved from early basic biological characteristics into engineered smart delivery platforms, with the application areas expanding from intestinal inflammation to neurological, metabolic, dermatological, and oncological diseases. This review systematically examines the core directions in this field. It compares the strengths and limitations of mainstream isolation methods and highlights the value of multi-omics integration, covering the molecular mechanisms of ferroptosis and gut microbiota regulation by PDEVs along with engineering strategies such as drug loading, surface modification, and membrane fusion. It also discusses the latest progress in frontier therapeutic applications of PDEVs, including cancer, inflammatory diseases, tissue regeneration and aesthetics, and neurological disorders. Finally, this review summarizes the key challenges confronting the field, including the lack of standardized protocols, production bottlenecks, and engineering obstacles. It also delineates future directions, including establishing international standardization definitions, advancing multi-omics and AI-driven mechanistic elucidation, developing scalable and efficient purification technologies, and executing systematic preclinical safety and pharmacokinetic evaluations to facilitate clinical translation.