{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T17:16:20Z","timestamp":1788455780800,"version":"build-2803163510"},"reference-count":102,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002471","name":"Dongguk University College of Medicine Research Fund","doi-asserted-by":"publisher","award":["K-2026-G0002-00007"],"award-info":[{"award-number":["K-2026-G0002-00007"]}],"id":[{"id":"10.13039\/501100002471","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Major depressive disorder remains a leading cause of disability worldwide, and the limited efficacy and delayed onset of conventional antidepressants have intensified interest in the microbiota\u2013gut\u2013brain axis as a source of therapeutic targets. Microbiota-associated candidates\u2014short-chain fatty acids, bile acid and tryptophan metabolites, and neuroactive amines\u2014show mood-relevant activity, yet almost none has reached the clinic. This review reframes that gap as a delivery problem. Rather than treating entry into the central nervous system as a universal requirement, we distinguish strategies intended for local intestinal, peripheral systemic, and direct central action, and we argue that delivery is a major but not exclusive translational bottleneck. We outline the barriers these agents face\u2014upper gastrointestinal loss, poor colonic targeting, rapid metabolite turnover, first-pass exposure, and the blood\u2013brain barrier\u2014and synthesize delivery strategies across two fronts. Colon-targeted systems are technically established but have been validated for non-depression indications, whereas brain-directed approaches\u2014bacterial extracellular vesicles, detoxified membrane-coated carriers, receptor-mediated transcytosis, and intranasal routes\u2014reach the brain mainly in selected preclinical models. We foreground a paradox: microbial extracellular vesicles are at once one of the better-documented bio-derived routes for brain exposure in preclinical studies and prominent drivers of neuroinflammation, which defines a risk\u2013opportunity continuum. We close with a route-specific validation roadmap encompassing quantitative exposure, target engagement, chronic efficacy, and safety.<\/jats:p>","DOI":"10.3390\/pharmaceutics18091112","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T16:21:21Z","timestamp":1788452481000},"page":"1112","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Delivering the Gut to the Brain: Drug Delivery Strategies for Microbiota-Derived Therapeutics in Depression"],"prefix":"10.3390","volume":"18","author":[{"given":"Yohan","family":"Seo","sequence":"first","affiliation":[{"name":"Department of Physiology, College of Medicine, Dongguk University, Gyeongju 38066, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chul Soon","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Bio-Nanomaterials, Bio Campus of Korea Polytechnics, Nonsan 32943, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"GBD 2019 Mental Disorders Collaborators (2022). 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