{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:07:05Z","timestamp":1784542025267,"version":"3.55.0"},"reference-count":150,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Crossing the blood\u2013brain barrier (BBB) remains a central obstacle in central nervous system (CNS) therapeutics. Hirudin, a 65-amino acid, disulfide-stabilized, direct thrombin inhibitor with a long history in Traditional Chinese Medicine, has shown compelling efficacy in thrombotic disorders and mounting neuroprotective activity in preclinical stroke models, with supportive clinical signals. Although few studies have directly quantified its BBB permeability, available evidence indicates low but measurable brain exposure under pathological conditions, likely via paracellular leakage rather than receptor-mediated transport. To extend its therapeutic reach in cerebrovascular diseases and mitigate bleeding risk, researchers have engineered hirudin using nanocarrier encapsulation, hydrogel-based delivery systems, prodrug strategies, and other methods to enhance targeting, prolong half-life, and localize activation. These approaches also enable synergistic combinations with established CNS drugs and may facilitate delivery of co-therapeutics to the brain. This review synthesizes current evidence for hirudin in stroke, neurodegeneration, psychiatric disorders, and brain tumors; evaluates its context-dependent BBB access; and outlines a translational agenda centered on quantitative brain pharmacokinetics, pathology-guided targeting, stimulus-responsive formulations, controlled clinical evaluation, and rigorous management of bleeding risk and chemistry, manufacturing, and controls (CMC) readiness.<\/jats:p>","DOI":"10.3390\/ijms27146388","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:32:54Z","timestamp":1784539974000},"page":"6388","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hirudin as a Therapeutic and Brain-Delivery Platform: From Stroke to Central Nervous System Disorders"],"prefix":"10.3390","volume":"27","author":[{"given":"Yufei","family":"Sun","sequence":"first","affiliation":[{"name":"School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4076-5609","authenticated-orcid":false,"given":"Qiang","family":"Fu","sequence":"additional","affiliation":[{"name":"Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunyao","family":"Deng","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7175-5166","authenticated-orcid":false,"given":"Hongjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6976-6157","authenticated-orcid":false,"given":"Zhong","family":"Zuo","sequence":"additional","affiliation":[{"name":"School of Pharmacy, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhonggui","family":"He","sequence":"additional","affiliation":[{"name":"Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6094-0438","authenticated-orcid":false,"given":"Zhijun","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"147937","DOI":"10.1016\/j.brainres.2022.147937","article-title":"Factors Influencing the Blood-Brain Barrier Permeability","volume":"1788","author":"Zhao","year":"2022","journal-title":"Brain Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Asimakidou, E., Tan, J.K.S., Zeng, J., and Lo, C.H. 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