{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T10:17:10Z","timestamp":1787912230932,"version":"build-2784847793"},"reference-count":63,"publisher":"Wiley","issue":"48","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["2662023PY019"],"award-info":[{"award-number":["2662023PY019"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Serine\/threonine\u2010proline (S\/T\u2010P) phosphorylation is a fundamental mechanism maintaining cellular homeostasis. Although glycogen synthase kinase 3\u03b2 (GSK3\u03b2) is a key regulator in ischemic stroke, the contribution of its proline\u2010directed kinase activity to cellular dysfunction and disease progression remains unclear. Here, we developed Nb.29E9, a nanobody that selectively targets the proline\u2010directed kinase domain of GSK3\u03b2. Under ischemic conditions, Nb.29E9 inhibited S\/T\u2010P phosphorylation of key substrates, including RNA\u2010binding motif protein 38 (RBM38), HIF1\u03b1, and p53, thereby enhancing neuronal and microglial viability while reducing oxidative stress and neuroinflammation. Phosphoproteomic analysis revealed broad reprogramming of S\/T\u2010P phosphorylation networks. In mice after ischemic injury, Nb.29E9 delivered via a brain\u2010penetrant, MMP\u20109\u2010responsive nanoparticle reduced infarct volume, restored neurovascular integrity, and improved motor function. Mechanistically, Nb.29E9 corrected pathological hyperphosphorylation of SMAD2\/3\u2010Thr8 (TGF\u03b2 signaling), calcium\/calmodulin\u2010dependent protein kinase kinase 2 (CAMKK2)\u2010Ser495 (AMPK pathway), and AKT1 substrate 1 (AKT1S1)\u2010Ser183 (mTORC1 regulation). These findings demonstrate that GSK3\u03b2\u2019s intrinsic proline\u2010directed kinase activity drives ischemic neurodegeneration, establishing its pathogenic role in vivo.<\/jats:p>","DOI":"10.1002\/advs.76004","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T10:26:59Z","timestamp":1781000819000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Brain\u2010Penetrant Nanobody Reveals GSK3\u03b2\u2010Driven Proline\u2010Directed Phosphorylation as a Master Regulator of Ischemic Neurodegeneration"],"prefix":"10.1002","volume":"13","author":[{"given":"Lan","family":"Li","sequence":"first","affiliation":[{"name":"College of Biomedicine and Health College of Life science and Technology Huazhong Agricultural University  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muyang","family":"Li","sequence":"additional","affiliation":[{"name":"College of 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