Cross-kingdom miRNA delivery by Panax notoginseng-derived EVs restores neuronal function after ischemic injury

The impermeability of the blood brain barrier (BBB) remains a major obstacle to effective treatment of neurological disorders, particularly ischemic stroke. Here, we show that plant-derived extracellular vesicles (PEVs) offer a promising strategy to overcome this barrier. Using an optimized high-yield extraction protocol, we isolated PEVs from four medicinal plants Panax ginseng, Panax notoginseng, Gastrodia elata, and Ligusticum chuanxiong. Among these, EVs derived from Panax notoginseng (NotoEVs) exhibited the strongest neuroprotective effects under hypoxic conditions in both in vitro and in vivo stroke models. Mechanistically, NotoEVs deliver conserved plant microRNAs to recipient neurons, where they suppress key stress granule nucleators (G3bp2, Ubap2l, Lsm14a), activate mTOR signaling, and promote mitochondrial stabilization via the BCL2 and TOM20 axis. This cross kingdom RNA delivery reprograms neuronal stress responses, reduces infarct volume, preserves neuronal morphology, and restores electrophysiological function. Together, our findings establish a scalable platform for plant-based nanotherapeutics and highlight the translational potential of NotoEVs for the treatment of ischemic stroke.