{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T14:00:21Z","timestamp":1781359221422,"version":"3.54.1"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>Extracellular vesicles (EVs) mediate intercellular communication by transferring bioactive molecules. While animal-derived EVs are well studied, plant-derived EVs (plant-EVs) are emerging as stable, low-immunogenic nanocarriers with therapeutic potential. <jats:italic>Platycladus orientalis<\/jats:italic> (L.) Franco, used in traditional medicine, contains neuroactive compounds. This study evaluated the effects of <jats:italic>P. orientalis<\/jats:italic> leaf-derived EVs in rodent models of anxiety, depression, and insomnia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>EVs were isolated by differential ultracentrifugation, characterized by electron microscopy and nanoparticle tracking analysis, and their bioactive components identified by GC -MS. Uptake was assessed in PC12 cells. Behavioral and biochemical effects were tested in mice subjected to chronic restraint stress (CRS), chronic unpredictable mild stress (CUMS), and para-chlorophenylalanine (PCPA)-induced insomnia. Key outcomes included social interaction, sucrose preference, Morris water maze performance, sleep parameters, neurotransmitter levels (5-HT, GABA), and inflammatory markers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>P. orientalis<\/jats:italic> EVs exhibited bilayer vesicle morphology (\u223c100 nm) and contained abundant volatile compounds, particularly \u03b1-pinene. They were internalized by PC12 cells and reduced corticosterone-induced injury. In vivo, intranasal EV administration alleviated anxiety-like behaviors in CRS mice, restored sucrose preference and cognition in CUMS mice, and improved sleep onset and duration in PCPA-induced insomnia. Across models, EVs normalized serum and hippocampal 5-HT and GABA levels, reduced pro-inflammatory cytokines (TNF-\u03b1, IL-6), and increased TGF-\u03b2 expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p><jats:italic>P. orientalis<\/jats:italic> leaf-derived EVs exert significant anxiolytic, antidepressant, and soporific effects through multimodal mechanisms involving neurotransmitter regulation and anti-inflammatory activity. Intranasal administration offers an effective strategy to bypass the blood -brain barrier, supporting the translational potential of plant-EVs as novel therapeutics for psychiatric disorders.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1693106","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T05:25:45Z","timestamp":1759123545000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Therapeutic potential of extracellular vesicles derived from Platycladus Orientalis leaf in treating anxiety, depression, and insomnia"],"prefix":"10.3389","volume":"16","author":[{"given":"Peiyu","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiyang","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoxin","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanjuan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faliang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaochang","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruijie","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.3390\/plants10081496","article-title":"Plant disease control efficacy of Platycladus orientalis and its antifungal compounds","volume":"10","author":"Bae","year":"2021","journal-title":"Plants (Basel)"},{"key":"B2","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1146\/annurev-genet-111523-102725","article-title":"The nature and nurture of extracellular vesicle-mediated signaling","volume":"58","author":"Buck","year":"2024","journal-title":"Annu. 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