Extracellular vesicles: Multi-source regulatory mechanisms in hippocampal homeostasis

Hippocampal health is pivotal for memory, emotional regulation, and cognition. Extracellular vesicles (EVs) facilitate intercellular and inter-organ communication by transporting bioactive cargos; however, traditional research often overlooks systemic influences on the hippocampus in favor of local microenvironmental changes. This review synthesizes evidence demonstrating that hippocampal homeostasis is modulated by the organism's systemic state-including aging, obesity, and immune status-via EVs. We detail mechanisms by which EVs from peripheral organs (adipose tissue, gut/microbiota, lung, bone, muscle, liver, kidney, heart, and spleen) and central nervous system resident cells (neurons, microglia, astrocytes, neural stem cells, and endothelial cells) regulate hippocampal function. These multi-source EVs precisely modulate neurogenesis, inflammatory responses, and synaptic plasticity. Furthermore, we highlight the emerging role of migrasomes as a specialized subset of EVs in this regulatory landscape. By mapping this comprehensive EV-mediated network, we provide a holistic perspective on the crosstalk between the systemic environment and the hippocampus, offering novel insights and therapeutic strategies for diseases associated with hippocampal dysfunction.