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It continues to present therapeutic challenges due to population heterogeneity in treatment response. This study investigates the unexplored role of metallothionein\u20102 (Mt2) in migraine pathophysiology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed the EGR1\u2010GFP reporter system to identify activated cortical cells induced by nitroglycerin (NTG). RNA sequencing of somatosensory activated cortex cells revealed marked Mt2 upregulation particularly in vascular endothelial cells. To elucidate Mt2's function in migraine pathogenesis, endothelial\u2010targeted nanoparticles encapsulating Mt2\u2010shRNA were engineered and administered via tail\u2010vein injection in migraine model mice. Behavioral assays assessed photophobia and hyperalgesia, while two\u2010photon microscopy evaluated cerebral vasodilation. Pathway enrichment analysis identified critical biological pathways linked to Mt2 activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Suppression of Mt2 in endothelial cells via shRNA nanoparticles alleviated migraine\u2010related behaviors, including photophobia and hyperalgesia. RNA\u2010seq and pathway analysis highlighted Mt2's involvement in cerebrovascular endothelial cell development, migration, and inflammation pathways. Crucially, two\u2010photon imaging demonstrated that downregulation of Mt2 markedly attenuated NTG\u2010induced cerebral vasodilation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study establishes Mt2 as a regulator of vascular tone and inflammatory signaling in migraine pathogenesis, proposing novel therapeutic targets. These findings provide insight in understanding the interplay between vascular dysfunction and migraine.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cns.70643","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T07:24:55Z","timestamp":1762413895000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Endothelial\u2010Targeted Metallothionein\u20102\n                    <scp>shRNA<\/scp>\n                    Nanoparticles Alleviate Migraine\u2010Like Symptoms"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2198-150X","authenticated-orcid":false,"given":"Chenlu","family":"Zhu","sequence":"first","affiliation":[{"name":"Headache Center, Department of Neurology, Beijing Tiantan Hospital Capital Medical University  Beijing China"},{"name":"Department of Neurology The First Affiliated Hospital of Shandong First Medical University &amp; 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