{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:58:50Z","timestamp":1792789130073,"version":"4.5.0"},"reference-count":103,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"China Academy of Chinese Medical Sciences","award":["CI2024D002"],"award-info":[{"award-number":["CI2024D002"]}],"id":[{"id":"https:\/\/ror.org\/042pgcv68","id-type":"ROR","asserted-by":"crossref"}]},{"name":"China Academy of Chinese Medical Sciences","award":["ZZ11-073"],"award-info":[{"award-number":["ZZ11-073"]}],"id":[{"id":"https:\/\/ror.org\/042pgcv68","id-type":"ROR","asserted-by":"crossref"}]},{"name":"China Academy of Chinese Medical Sciences","award":["ZZ13-YQ-018"],"award-info":[{"award-number":["ZZ13-YQ-018"]}],"id":[{"id":"https:\/\/ror.org\/042pgcv68","id-type":"ROR","asserted-by":"crossref"}]},{"award":["CI2024D002"],"award-info":[{"award-number":["CI2024D002"]}],"id":[{"id":"https:\/\/ror.org\/042pgcv68","id-type":"ROR","asserted-by":"publisher"}]},{"award":["ZZ11-073"],"award-info":[{"award-number":["ZZ11-073"]}],"id":[{"id":"https:\/\/ror.org\/042pgcv68","id-type":"ROR","asserted-by":"publisher"}]},{"award":["ZZ13-YQ-018"],"award-info":[{"award-number":["ZZ13-YQ-018"]}],"id":[{"id":"https:\/\/ror.org\/042pgcv68","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Intravenous thrombolysis and endovascular thrombectomy (EVT) have increased large-vessel recanalization in acute ischemic stroke, yet macrovascular reopening does not ensure tissue reperfusion or functional recovery. Microvascular no-reflow, blood\u2013brain barrier failure, oxidative injury, thromboinflammation, edema, and hemorrhagic transformation sustain a recanalization-to-recovery gap. Classical neuroprotection failed because of mismatches in models, timing, brain exposure, patient selection, and endpoints, and because ischemic injury was reduced to a single neuronal pathway. Cerebroprotection in the reperfusion era should target the neurovascular unit: delaying penumbral collapse before recanalization, limiting oxidative and vascular injury during thrombectomy, and restoring microcirculatory and barrier function afterwards. Recent trials show a differentiated landscape. ESCAPE-NEXT and RODIN were neutral; TASTE-2 suggested a borderline overall effect and imaging-defined heterogeneity for edaravone dexborneol; BAST supported potential benefit from butylphthalide; and the positive EMPHASIS trial contrasted with neutral EVT-specific MIST-A findings for minocycline. We organize mechanisms and interventions along the macrovascular recanalization\u2013tissue reperfusion\u2013neurovascular-unit preservation\u2013functional recovery continuum, stratify evidence across pharmacological, physiological, delivery, natural-product, and cell\/extracellular-vesicle strategies, and propose a precision framework integrating tissue and target windows, reperfusion status, and measurable treatment response. Next-generation trials should combine target engagement, imaging enrichment, prespecified biomarker interactions, and adaptive designs. Current evidence supports redesigning cerebroprotection, not adopting any candidate as a universal adjunct to reperfusion.<\/jats:p>","DOI":"10.3390\/biom16091346","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T07:58:59Z","timestamp":1789545539000},"page":"1346","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond Recanalization: Neurovascular Unit Protection and Precision Adjunctive Therapy for Ischemic Stroke in the Reperfusion Era"],"prefix":"10.3390","volume":"16","author":[{"given":"Xusheng","family":"Wu","sequence":"first","affiliation":[{"name":"Clinical Medical College, Qinghai University, Xining 810016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Xing","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Qinghai University, Xining 810016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Medicine, Medical College, Qinghai University, Xining 810001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianhui","family":"Wang","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Qinghai University, Xining 810016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingjiang","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Guang\u2019anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1016\/S0140-6736(16)00163-X","article-title":"Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials","volume":"387","author":"Goyal","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1001\/jama.2016.13647","article-title":"Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: A meta-analysis","volume":"316","author":"Saver","year":"2016","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Shen, H., Killingsworth, M.C., and Bhaskar, S.M.M. (2023). Comprehensive meta-analysis of futile recanalization in acute ischemic stroke patients undergoing endovascular thrombectomy: Prevalence, factors, and clinical outcomes. Life, 13.","DOI":"10.3390\/life13101965"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s42466-020-00060-6","article-title":"Recovery from stroke: Current concepts and future perspectives","volume":"2","author":"Grefkes","year":"2020","journal-title":"Neurol. Res. Pract."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1093\/brain\/awr033","article-title":"Reorganization of cerebral networks after stroke: New insights from neuroimaging with connectivity approaches","volume":"134","author":"Grefkes","year":"2011","journal-title":"Brain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1038\/nrneurol.2017.34","article-title":"Restoring brain function after stroke\u2014Bridging the gap between animals and humans","volume":"13","author":"Ward","year":"2017","journal-title":"Nat. Rev. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s41073-019-0064-8","article-title":"SANRA\u2014A scale for the quality assessment of narrative review articles","volume":"4","author":"Baethge","year":"2019","journal-title":"Res. Integr. Peer. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1161\/STROKEAHA.118.023927","article-title":"Stroke Treatment Academic Industry Roundtable X: Brain cytoprotection therapies in the reperfusion era","volume":"50","author":"Savitz","year":"2019","journal-title":"Stroke"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3063","DOI":"10.1161\/STROKEAHA.121.034947","article-title":"Top priorities for cerebroprotective studies\u2014A paradigm shift: Report from STAIR XI","volume":"52","author":"Lyden","year":"2021","journal-title":"Stroke"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.neuron.2017.07.030","article-title":"The neurovascular unit coming of age: A journey through neurovascular coupling in health and disease","volume":"96","author":"Iadecola","year":"2017","journal-title":"Neuron"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/s41572-019-0118-8","article-title":"Ischaemic stroke","volume":"5","author":"Campbell","year":"2019","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/nrn1106","article-title":"Mechanisms, challenges and opportunities in stroke","volume":"4","author":"Lo","year":"2003","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.neuron.2010.07.002","article-title":"The science of stroke: Mechanisms in search of treatments","volume":"67","author":"Moskowitz","year":"2010","journal-title":"Neuron"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1002\/ana.20741","article-title":"1,026 experimental treatments in acute stroke","volume":"59","author":"Macleod","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1038\/sj.jcbfm.9600298","article-title":"Bench to bedside: The quest for quality in experimental stroke research","volume":"26","author":"Dirnagl","year":"2006","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1038\/jcbfm.2010.66","article-title":"Different strokes for different folks: The rich diversity of animal models of focal cerebral ischemia","volume":"30","author":"Howells","year":"2010","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e50","DOI":"10.1161\/STROKEAHA.108.525386","article-title":"Good laboratory practice: Preventing introduction of bias at the bench","volume":"40","author":"Macleod","year":"2009","journal-title":"Stroke"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/S0140-6736(20)30258-0","article-title":"Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): A multicentre, double-blind, randomised controlled trial","volume":"395","author":"Hill","year":"2020","journal-title":"Lancet"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1136\/neurintsurg-2020-016118","article-title":"Proteomic changes in intracranial blood during human ischemic stroke","volume":"13","author":"Maglinger","year":"2021","journal-title":"J. NeuroInterventional Surg."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Martha, S.R., Cheng, Q., Fraser, J.F., Gong, L., Collier, L.A., Davis, S.M., Lukins, D., Alhajeri, A., Grupke, S., and Pennypacker, K.R. (2020). Expression of cytokines and chemokines as predictors of stroke outcomes in acute ischemic stroke. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.01391"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/S0140-6736(25)00194-1","article-title":"Efficacy and safety of nerinetide in acute ischaemic stroke in patients undergoing endovascular thrombectomy without previous thrombolysis (ESCAPE-NEXT): A multicentre, double-blind, randomised controlled trial","volume":"405","author":"Hill","year":"2025","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3250","DOI":"10.1161\/STROKEAHA.122.039649","article-title":"Nelonemdaz for patients with acute ischemic stroke undergoing endovascular reperfusion therapy: A randomized phase II trial","volume":"53","author":"Hong","year":"2022","journal-title":"Stroke"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e2456535","DOI":"10.1001\/jamanetworkopen.2024.56535","article-title":"Nelonemdaz and patients with acute ischemic stroke and mechanical reperfusion: The RODIN randomized clinical trial","volume":"8","author":"Kang","year":"2025","journal-title":"JAMA Netw. Open"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1001\/jamaneurol.2023.5716","article-title":"Sublingual edaravone dexborneol for the treatment of acute ischemic stroke: The TASTE-SL randomized clinical trial","volume":"81","author":"Fu","year":"2024","journal-title":"JAMA Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e086850","DOI":"10.1136\/bmj-2025-086850","article-title":"Edaravone dexborneol versus placebo on functional outcomes in patients with acute ischaemic stroke undergoing endovascular thrombectomy (TASTE-2): Randomised controlled trial","volume":"392","author":"Wang","year":"2026","journal-title":"BMJ"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/S1474-4422(14)70054-7","article-title":"Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): A randomised, double-blind phase 2b\/3 trial","volume":"13","author":"Chamorro","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.nbd.2008.08.005","article-title":"Blood-brain barrier tight junction permeability and ischemic stroke","volume":"32","author":"Sandoval","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3323","DOI":"10.1161\/STROKEAHA.110.608257","article-title":"Blood-brain barrier breakdown in acute and chronic cerebrovascular disease","volume":"42","author":"Yang","year":"2011","journal-title":"Stroke"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3292","DOI":"10.1002\/acn3.52236","article-title":"Blood-brain barrier profile pretreatment is associated with hemorrhagic transformation after endovascular reperfusion","volume":"11","author":"Leigh","year":"2024","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s12987-024-00537-5","article-title":"Analysis of ischemic stroke-mediated effects on blood-brain barrier properties along the arteriovenous axis assessed by intravital two-photon imaging","volume":"21","author":"Protzmann","year":"2024","journal-title":"Fluids Barriers CNS"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Arba, F., Rinaldi, C., Caimano, D., Vit, F., Busto, G., and Fainardi, E. (2021). Blood-brain barrier disruption and hemorrhagic transformation in acute ischemic stroke: Systematic review and meta-analysis. Front. Neurol., 11.","DOI":"10.3389\/fneur.2020.594613"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Liang, Y., Yu, Y., Liu, J., Li, X., Chen, X., Zhou, H., and Guo, Z.-N. (2024). Blood-brain barrier disruption and hemorrhagic transformation in acute stroke before endovascular reperfusion therapy. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1349369"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1161\/STROKEAHA.111.632356","article-title":"The hyperintense acute reperfusion marker on fluid-attenuated inversion recovery magnetic resonance imaging is caused by gadolinium in the cerebrospinal fluid","volume":"43","author":"Struffert","year":"2012","journal-title":"Stroke"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"107216","DOI":"10.1016\/j.jstrokecerebrovasdis.2023.107216","article-title":"The clinical utility of dual-energy CT in post-thrombectomy care: Part 2, the predictive value of contrast density and volume for delayed hemorrhagic transformation","volume":"32","author":"Ahn","year":"2023","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1016\/S1474-4422(24)00425-3","article-title":"Intravenous glibenclamide for cerebral oedema after large hemispheric stroke (CHARM): A phase 3, double-blind, placebo-controlled, randomised trial","volume":"23","author":"Sheth","year":"2024","journal-title":"Lancet Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1007\/s13311-016-0483-x","article-title":"Inflammation and stroke: An overview","volume":"13","author":"Anrather","year":"2016","journal-title":"Neurotherapeutics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1002\/ana.24993","article-title":"Neutrophil extracellular traps in ischemic stroke thrombi","volume":"82","author":"Laridan","year":"2017","journal-title":"Ann. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1007\/s11239-024-03004-y","article-title":"Assessment of associations between neutrophil extracellular trap biomarkers in blood and thrombi in acute ischemic stroke patients","volume":"57","author":"Baumann","year":"2024","journal-title":"J. Thromb. Thrombolysis"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e154225","DOI":"10.1172\/JCI154225","article-title":"Neutrophil extracellular traps regulate ischemic stroke brain injury","volume":"132","author":"Denorme","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1001\/jamaneurol.2023.1660","article-title":"Safety and efficacy of ApTOLL in patients with ischemic stroke undergoing endovascular treatment","volume":"80","author":"Cotgreave","year":"2023","journal-title":"JAMA Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1161\/CIRCULATIONAHA.115.016371","article-title":"Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke: A pilot trial","volume":"132","author":"Zhu","year":"2015","journal-title":"Circulation"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.1038\/mp.2017.171","article-title":"Tau-mediated iron export prevents ferroptotic damage after ischemic stroke","volume":"22","author":"Tuo","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"101262","DOI":"10.1016\/j.gendis.2024.101262","article-title":"Iron promotes both ferroptosis and necroptosis in the early stage of reperfusion in ischemic stroke","volume":"11","author":"Du","year":"2024","journal-title":"Genes Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6071","DOI":"10.7150\/thno.100090","article-title":"Hypoxanthine is a metabolic biomarker for inducing GSDME-dependent pyroptosis of endothelial cells during ischemic stroke","volume":"14","author":"Ye","year":"2024","journal-title":"Theranostics"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1161\/STROKEAHA.123.044240","article-title":"No-reflow post-recanalization in acute ischemic stroke: Mechanisms, measurements, and molecular markers","volume":"54","author":"Sperring","year":"2023","journal-title":"Stroke"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1177\/0271678X231216766","article-title":"Progressive microvascular failure in acute ischemic stroke: A systematic review, meta-analysis, and time-course analysis","volume":"44","author":"Tudor","year":"2024","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1002\/ana.27073","article-title":"Comparison of perfusion imaging definitions of the no-reflow phenomenon after thrombectomy\u2014What is the best perfusion imaging definition?","volume":"96","author":"Mutimer","year":"2024","journal-title":"Ann. Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e14631","DOI":"10.1111\/cns.14631","article-title":"No-reflow after stroke reperfusion therapy: An emerging phenomenon to be explored","volume":"30","author":"Jia","year":"2024","journal-title":"CNS Neurosci. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1038\/nm.2022","article-title":"Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery","volume":"15","author":"Yemisci","year":"2009","journal-title":"Nat. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"108260","DOI":"10.1016\/j.celrep.2020.108260","article-title":"Neutrophils obstructing brain capillaries are a major cause of no-reflow in ischemic stroke","volume":"33","author":"Binder","year":"2020","journal-title":"Cell Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1093\/brain\/awad401","article-title":"Continued dysfunction of capillary pericytes promotes no-reflow after experimental stroke in vivo","volume":"147","author":"Shrouder","year":"2024","journal-title":"Brain"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1177\/17474930231180434","article-title":"No-reflow phenomenon in stroke patients: A systematic literature review and meta-analysis of clinical data","volume":"19","author":"Mujanovic","year":"2024","journal-title":"Int. J. Stroke"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1177\/0271678X20954929","article-title":"Tissue no-reflow despite full recanalization following thrombectomy for anterior circulation stroke with proximal occlusion: A clinical study","volume":"41","author":"Charron","year":"2021","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3939","DOI":"10.1007\/s10072-023-06879-6","article-title":"No-reflow phenomenon in acute ischemic stroke: An angiographic evaluation","volume":"44","author":"Nicolini","year":"2023","journal-title":"Neurol. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1161\/STROKEAHA.120.029212","article-title":"Computed tomography perfusion after thrombectomy: An immediate surrogate marker of outcome after recanalization in acute stroke","volume":"51","author":"Rubiera","year":"2020","journal-title":"Stroke"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1161\/STROKEAHA.124.049574","article-title":"Persistent tissue-level hypoperfusion (no-reflow) negates the clinical benefit of successful thrombectomy","volume":"56","author":"Rivet","year":"2025","journal-title":"Stroke"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/S0140-6736(25)00193-X","article-title":"Efficacy and safety of intravenous nerinetide initiated by paramedics in the field for acute cerebral ischaemia within 3 h of symptom onset (FRONTIER): A phase 2, multicentre, randomised, double-blind, placebo-controlled study","volume":"405","author":"Christenson","year":"2025","journal-title":"Lancet"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1001\/jamaneurol.2023.1871","article-title":"Efficacy and safety of butylphthalide in patients with acute ischemic stroke: A randomized clinical trial","volume":"80","author":"Wang","year":"2023","journal-title":"JAMA Neurol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/S0140-6736(25)01862-8","article-title":"Efficacy and safety of minocycline in patients with acute ischaemic stroke (EMPHASIS): A multicentre, double-blind, randomised controlled trial","volume":"407","author":"Lu","year":"2026","journal-title":"Lancet"},{"key":"ref_60","first-page":"101898","article-title":"Efficacy and safety of minocycline on patients with acute anterior circulation ischaemic stroke undergoing mechanical thrombectomy (MIST-A): A multicentre, prospective, randomised, open-label, blinded-endpoint, phase 2 trial","volume":"71","author":"Zhang","year":"2026","journal-title":"Lancet Reg. Health West Pac."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2422","DOI":"10.1161\/STROKEAHA.124.048917","article-title":"Changes in infarct volume and cerebral edema after mechanical thrombectomy in patients with stroke randomized to ApTOLL or placebo: A secondary analysis of APRIL trial","volume":"56","author":"Molina","year":"2025","journal-title":"Stroke"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1002\/ana.25383","article-title":"Final results of the RHAPSODY trial: A multi-center, phase 2 trial using a continual reassessment method to determine the safety and tolerability of 3K3A-APC, a recombinant variant of human activated protein C, in combination with tissue plasminogen activator, mechanical thrombectomy or both in moderate to severe acute ischemic stroke","volume":"85","author":"Lyden","year":"2019","journal-title":"Ann. Neurol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1056\/NEJMoa1408827","article-title":"Prehospital use of magnesium sulfate as neuroprotection in acute stroke","volume":"372","author":"Saver","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1016\/S1474-4422(16)30196-X","article-title":"Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): A randomised, double-blind, placebo-controlled phase 2 trial","volume":"15","author":"Sheth","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1002\/ana.25352","article-title":"Fingolimod enhances the efficacy of delayed alteplase administration in acute ischemic stroke","volume":"84","author":"Tian","year":"2018","journal-title":"Ann. Neurol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1001\/jama.2023.16893","article-title":"Remote ischemic conditioning for acute stroke: The RESIST randomized clinical trial","volume":"330","author":"Blauenfeldt","year":"2023","journal-title":"JAMA"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2888","DOI":"10.1161\/STROKEAHA.116.014200","article-title":"Results of the ICTuS 2 trial (Intravascular Cooling in the Treatment of Stroke 2)","volume":"47","author":"Lyden","year":"2016","journal-title":"Stroke"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/S0140-6736(24)02809-5","article-title":"Normobaric hyperoxia combined with endovascular treatment for acute ischaemic stroke in China (OPENS-2 trial): A multicentre, randomised, single-blind, sham-controlled trial","volume":"405","author":"Li","year":"2025","journal-title":"Lancet"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1001\/jama.2022.13123","article-title":"Effect of remote ischemic conditioning vs usual care on neurologic function in patients with acute moderate ischemic stroke: RICAMIS","volume":"328","author":"Chen","year":"2022","journal-title":"JAMA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"937","DOI":"10.5551\/jat.66105","article-title":"Remote ischemic conditioning for acute ischemic stroke: The RICAIS randomized clinical trial","volume":"33","author":"Kitagawa","year":"2026","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1111\/ijs.12294","article-title":"EuroHYP-1: European multicenter, randomized, phase III clinical trial of therapeutic hypothermia plus best medical treatment vs. best medical treatment alone for acute ischemic stroke","volume":"9","author":"Macleod","year":"2014","journal-title":"Int. J. Stroke"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e824","DOI":"10.1212\/WNL.0000000000201592","article-title":"Normobaric hyperoxia combined with endovascular treatment for patients with acute ischemic stroke: A randomized controlled clinical trial","volume":"99","author":"Li","year":"2022","journal-title":"Neurology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1177\/17474930231185275","article-title":"Penumbral Rescue by normobaric O = O administration in patients with ischemic stroke and target mismatch profile (PROOF): Study protocol of a phase IIb trial","volume":"19","author":"Poli","year":"2024","journal-title":"Int. J. Stroke"},{"key":"ref_74","first-page":"145","article-title":"Nanotechnology approaches to drug delivery for the treatment of ischemic stroke","volume":"43","author":"Peng","year":"2025","journal-title":"Bioact. Mater."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Prego-Dom\u00ednguez, J., Laso-Garc\u00eda, F., Palomar-Alonso, N., P\u00e9rez-Mato, M., L\u00f3pez-Arias, E., Dopico-L\u00f3pez, A., Hervella, P., Guti\u00e9rrez-Fern\u00e1ndez, M., de Leci\u00f1ana, M.A., and Polo, E. (2025). Nanoparticles for thrombolytic therapy in ischemic stroke: A systematic review and meta-analysis of preclinical studies. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17020208"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.4103\/NRR.NRR-D-24-01383","article-title":"Drug delivery strategies for neuroprotective therapy in ischemic stroke: Application of nanotechnology","volume":"21","author":"Jiang","year":"2026","journal-title":"Neural Regen. Res."},{"key":"ref_77","first-page":"CD004955","article-title":"Puerarin for ischaemic stroke","volume":"2","author":"Liu","year":"2016","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Zhang, L., Ma, J., Yang, F., Li, S., Ma, W., Chang, X., and Yang, L. (2022). Neuroprotective effects of quercetin on ischemic stroke: A literature review. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.854249"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/S1474-4422(17)30046-7","article-title":"Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): A randomised, double-blind, placebo-controlled, phase 2 trial","volume":"16","author":"Hess","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1001\/jamaneurol.2023.5200","article-title":"Allogeneic stem cell therapy for acute ischemic stroke: The phase 2\/3 TREASURE randomized clinical trial","volume":"81","author":"Houkin","year":"2024","journal-title":"JAMA Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1093\/stcltm\/szae040","article-title":"Efficacy and safety of mesenchymal stem cell therapies for ischemic stroke: A systematic review and meta-analysis","volume":"13","author":"Shen","year":"2024","journal-title":"Stem Cells Transl. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"111219","DOI":"10.1016\/j.brainresbull.2025.111219","article-title":"Therapeutic potential of mesenchymal stem cell-derived extracellular vesicles in ischemic stroke: A meta-analysis of preclinical studies","volume":"221","author":"Zhang","year":"2025","journal-title":"Brain Res. Bull."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Lee, J., Geum, D., Park, D.H., and Kim, J.H. (2024). Molecular targeting of ischemic stroke: The promise of na\u00efve and engineered extracellular vesicles. Pharmaceutics, 16.","DOI":"10.20944\/preprints202411.0189.v1"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Goo, J., Lee, Y., Lee, J., Kim, I.-S., and Jeong, C. (2024). Extracellular vesicles in therapeutics: A comprehensive review on applications, challenges, and clinical progress. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16030311"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e12404","DOI":"10.1002\/jev2.12404","article-title":"Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches","volume":"13","author":"Welsh","year":"2024","journal-title":"J. Extracell. Vesicles"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1007\/s11095-024-03757-4","article-title":"Quality and safety considerations for therapeutic products based on extracellular vesicles","volume":"41","author":"Takakura","year":"2024","journal-title":"Pharm. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"100278","DOI":"10.1016\/j.jlb.2024.100278","article-title":"Global requirements for manufacturing and validation of clinical grade extracellular vesicles","volume":"6","author":"Thakur","year":"2024","journal-title":"J. Liq. Biopsy"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Lu, J., Mei, Q., Hou, X., Manaenko, A., Zhou, L., Liebeskind, D.S., Zhang, J.H., Li, Y., and Hu, Q. (2021). Imaging acute stroke: From one-size-fits-all to biomarkers. Front. Neurol., 12.","DOI":"10.3389\/fneur.2021.697779"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.3174\/ajnr.A9095","article-title":"Neuroimaging predictors of futile recanalization in anterior circulation stroke: A systematic review and meta-analysis","volume":"47","author":"Kiani","year":"2026","journal-title":"Am. J. Neuroradiol."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Rahmig, J., Chanpura, A., Schultz, A., Barone, F.C., Gustafson, D., and Baird, A.E. (2024). Blood-based protein biomarkers during the acute ischemic stroke treatment window: A systematic review. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1411307"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.1177\/0271678X231172520","article-title":"Quantification and prospective evaluation of serum NfL and GFAP as blood-derived biomarkers of outcome in acute ischemic stroke patients","volume":"43","author":"Ferrari","year":"2023","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1177\/23969873241234436","article-title":"Incremental value of serum neurofilament light chain and glial fibrillary acidic protein as blood-based biomarkers for predicting functional outcome in severe acute ischemic stroke","volume":"9","author":"Vollmuth","year":"2024","journal-title":"Eur. Stroke J."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Lin, K., Wang, Y., Zhao, W., Zheng, Y., Sun, X., Fang, L., Fu, Y., Wang, N., and Lin, Q. (2025). Local cerebral neurofilament light chain during acute stage is associated with clinical outcomes in stroke patients receiving endovascular thrombectomy. BMC Neurol., 25.","DOI":"10.1186\/s12883-025-04290-6"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"105095","DOI":"10.1016\/j.ebiom.2024.105095","article-title":"MMP-9 release into collateral blood vessels before endovascular thrombectomy to assess the risk of major intracerebral haemorrhages and poor outcome for acute ischaemic stroke: A proof-of-concept study","volume":"103","author":"Kollikowski","year":"2024","journal-title":"EBioMedicine"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"eadg1323","DOI":"10.1126\/scitranslmed.adg1323","article-title":"Integrating spatial and single-cell transcriptomics to characterize the molecular and cellular architecture of the ischemic mouse brain","volume":"16","author":"Han","year":"2024","journal-title":"Sci. Transl. Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/s41590-023-01711-x","article-title":"Analysis of brain and blood single-cell transcriptomics in acute and subacute phases after experimental stroke","volume":"25","author":"Shahanoor","year":"2024","journal-title":"Nat. Immunol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"4","DOI":"10.5469\/neuroint.2025.00052","article-title":"Application of artificial intelligence in acute ischemic stroke: A scoping review","volume":"20","author":"Heo","year":"2025","journal-title":"Neurointervention"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"107890","DOI":"10.1016\/j.jstrokecerebrovasdis.2024.107890","article-title":"Ensemble machine learning to predict futile recanalization after mechanical thrombectomy based on non-contrast CT imaging","volume":"33","author":"Cavallo","year":"2024","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/s41591-024-02902-1","article-title":"Causal machine learning for predicting treatment outcomes","volume":"30","author":"Feuerriegel","year":"2024","journal-title":"Nat. Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1002\/psp4.12715","article-title":"Heterogeneous treatment effect analysis based on machine-learning methodology","volume":"10","author":"Gong","year":"2021","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1007\/s10488-023-01303-9","article-title":"A tutorial introduction to heterogeneous treatment effect estimation with meta-learners","volume":"51","author":"Salditt","year":"2024","journal-title":"Adm. Policy Ment. Health"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"e12","DOI":"10.1161\/STROKEAHA.125.052056","article-title":"Preclinical Ischemic Stroke Multicenter Trials (PRISM) Collective statement: Opportunities, challenges, and recommendations for a new era","volume":"57","author":"Ayata","year":"2026","journal-title":"Stroke"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1161\/STROKEAHA.118.021424","article-title":"STAIR X: Emerging considerations in developing and evaluating new stroke therapies","volume":"49","author":"Liebeskind","year":"2018","journal-title":"Stroke"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/9\/1346\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T04:15:21Z","timestamp":1789704921000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/9\/1346"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,16]]},"references-count":103,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["biom16091346"],"URL":"https:\/\/doi.org\/10.3390\/biom16091346","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,16]]}}}