Plant-Derived Nanovesicles for Ischemic Stroke Therapy via the Gut Microbiota-Gut-Brain Axis: A New Paradigm of Systemic Regulation

Abstract: Ischemic stroke (IS) is a globally significant disease with complex pathological mechanisms. Traditional therapeutic strategies centered on central nervous system-targeted delivery face substantial limitations due to the presence of the blood-brain barrier (BBB) and the multifactorial nature of the disease. In recent years, the gut microbiota-gut-brain axis, which elucidates the multi-pathway dialogue between the gut and the brain, has provided a novel systemic intervention perspective for IS treatment. In this context, Plant-Derived Nanovesicles (PDNVs), a class of natural nanocarriers derived from plants, have emerged prominently due to their inherent multi-component synergistic properties, excellent biocompatibility, and cross-kingdom regulatory capabilities. Critically, IS itself rapidly induces gut dysbiosis and barrier disruption, creating a vicious cycle that amplifies neuroinflammation—a pathological feature shared with other inflammatory conditions such as colitis and Inflammatory bowel disease. In this context, PDNVs, a class of natural nanocarriers derived from plants, have emerged prominently due to their inherent multi-component synergistic properties, excellent biocompatibility, and cross-kingdom regulatory capabilities. Drawing on mechanistic insights from these related disease models, this article systematically discusses the multi-level integrated mechanism of PDNVs as novel “functional messengers”, involving reshaping the gut microenvironment, mediating systemic metabolic-immune signals, and ultimately synergistically activating the central nervous repair network, thereby offering a new paradigm for IS therapy. This review not only summarizes the mechanisms of action of PDNVs but also systematically constructs a framework and strategy for their translation from experimental research to clinical application. Highlighting critical hurdles such as the need for standardized production and rigorous quality control to ensure batch-to-batch consistency. Diagram: stroke impacts brain-gut axis, therapy limits, plant nanovesicles aid gut balance.The diagram illustrates the impact of ischemic stroke on the brain-gut axis and potential therapeutic interventions. It begins with the brain experiencing an ischemic stroke, leading to stroke-associated intestinal injury and a leaky gut. Bidirectional communication is shown between the brain and gut. Therapeutic bottlenecks are highlighted, indicating challenges in treatment. Intact plant-derived nanovesicles are shown being orally administered, maintaining remarkable stability in the stomach. These nanovesicles cross the blood-brain barrier and produce beneficial metabolites, promoting gut homeostasis. The neurovascular unit is depicted as being repaired through these interventions. Keywords: ischemic stroke, plant-derived nanovesicles, gut microbiota-gut-brain axis, systemic regulation, drug delivery, neuroinflammation