Toxicology and biodistribution of plant-derived extracellular vesicles for drug delivery: Quality control, safety mechanisms, and translational testing priorities.

Plant-derived extracellular vesicles and plant-derived exosome-like nanoparticles are increasingly investigated as natural nanocarriers for drug delivery and as bioactive materials with intrinsic therapeutic potential. However, their translational development is limited by unresolved questions surrounding safety, biodistribution, product identity, and batch consistency. In this review, we synthesize current knowledge on the toxicology and biodistribution of plant-derived extracellular vesicle products, with emphasis on route-dependent exposure, barrier interactions, immune recognition, hemocompatibility, microbiome effects, and off-target organ accumulation. We argue that an edible plant origin should not be considered a surrogate for safety, particularly when products are administered at high doses, repeatedly, or through non-oral routes. We further identify quality control as a central determinant of both efficacy and safety, because plant source, growth conditions, harvest timing, isolation workflow, storage, and co-isolated contaminants can substantially alter vesicle composition and biological activity. To address these challenges, we propose a translational framework that integrates chemistry, manufacturing, and control principles with route-specific nonclinical toxicology testing and mechanism-linked potency assays. The framework highlights minimum expectations for identity, purity, potency, stability, and contaminant testing, including microbial burden, endotoxin-like activity, pesticide residues, and heavy metals. We also outline research priorities needed for regulatory-grade development, including harmonized nomenclature, reference materials, orthogonal characterization strategies, and mechanistic studies that distinguish vesicle-intrinsic effects from cargo- or impurity-driven toxicity. Collectively, this review positions toxicology and product quality as the key organizing principles for the safe and reproducible development of plant-derived extracellular vesicles in drug delivery.