{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T01:41:18Z","timestamp":1791855678468,"version":"4.3.4"},"reference-count":76,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":67,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82372187"],"award-info":[{"award-number":["82372187"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82472219"],"award-info":[{"award-number":["82472219"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82402556"],"award-info":[{"award-number":["82402556"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100021171","name":"Guangdong Basic and Applied Basic Research Foundation","doi-asserted-by":"crossref","award":["2024A1515013136"],"award-info":[{"award-number":["2024A1515013136"]}],"id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Nanobiotechnol"],"DOI":"10.1186\/s12951-026-04643-4","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T15:33:13Z","timestamp":1780587193000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["M2 microglia-derived migrasome-enriched extracellular vesicles restore mitochondrial homeostasis to orchestrate neurovascular unit recovery after ischemic stroke"],"prefix":"10.1186","volume":"24","author":[{"given":"Yuanjia","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leyi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqian","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jierui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefeng","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajing","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanchenye","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaorong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongxing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,4]]},"reference":[{"key":"4643_CR1","first-page":"e41","volume":"151","author":"SS Martin","year":"2025","unstructured":"Martin SS, Aday AW, Allen NB, Almarzooq ZI, Anderson CAM, Arora P, Avery CL, Baker-Smith CM, Bansal N, Beaton AZ, et al. 2025 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association. Circulation. 2025;151:e41\u2013660.","journal-title":"Circulation"},{"key":"4643_CR2","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1038\/s41392-023-01688-x","volume":"9","author":"M Zhang","year":"2024","unstructured":"Zhang M, Liu Q, Meng H, Duan H, Liu X, Wu J, Gao F, Wang S, Tan R, Yuan J. Ischemia-reperfusion injury: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther. 2024;9:12.","journal-title":"Signal Transduct Target Ther"},{"key":"4643_CR3","doi-asserted-by":"publisher","first-page":"2435","DOI":"10.1021\/acsnano.5c20015","volume":"20","author":"R Tian","year":"2026","unstructured":"Tian R, Ma H, Ren J, Li Y, Zhang Z, Xu Z, He L, Zhu C, Xu J, Yu S, et al. Selenium-Containing Nanoscale Hydrogen-Bonded Organic Framework Nanozymes for Multienzyme Cascade Antioxidant-Targeted Therapy of Cerebral Ischemia-Reperfusion Injury. ACS Nano. 2026;20:2435\u201350.","journal-title":"ACS Nano"},{"key":"4643_CR4","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/s41583-025-00985-4","volume":"27","author":"N McMillan","year":"2026","unstructured":"McMillan N, McMillan A, Kiliaan P, Yahya T, Thakkar R, Weiner H, Smirnakis S, Yavagal D, Izzy S. Stem cell-mediated recovery in stroke: partnering with the immune system. Nat Rev Neurosci. 2026;27:23\u201343.","journal-title":"Nat Rev Neurosci"},{"key":"4643_CR5","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1002\/glia.24634","volume":"73","author":"A McDonough","year":"2025","unstructured":"McDonough A, Weinstein JR. Glial \u2018omics in ischemia: Acute stroke and chronic cerebral small vessel disease. Glia. 2025;73:495\u2013518.","journal-title":"Glia"},{"key":"4643_CR6","doi-asserted-by":"publisher","first-page":"1058","DOI":"10.1016\/S1474-4422(19)30078-X","volume":"18","author":"K Shi","year":"2019","unstructured":"Shi K, Tian DC, Li ZG, Ducruet AF, Lawton MT, Shi FD. Global brain inflammation in stroke. Lancet Neurol. 2019;18:1058\u201366.","journal-title":"Lancet Neurol"},{"key":"4643_CR7","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1038\/s41582-022-00703-z","volume":"18","author":"S Tiedt","year":"2022","unstructured":"Tiedt S, Buchan AM, Dichgans M, Lizasoain I, Moro MA, Lo EH. The neurovascular unit and systemic biology in stroke - implications for translation and treatment. Nat Rev Neurol. 2022;18:597\u2013612.","journal-title":"Nat Rev Neurol"},{"key":"4643_CR8","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.cytogfr.2024.06.002","volume":"78","author":"S Kumari","year":"2024","unstructured":"Kumari S, Dhapola R, Sharma P, Nagar P, Medhi B, HariKrishnaReddy D. The impact of cytokines in neuroinflammation-mediated stroke. Cytokine Growth Factor Rev. 2024;78:105\u201319.","journal-title":"Cytokine Growth Factor Rev"},{"key":"4643_CR9","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1038\/nm.2399","volume":"17","author":"C Iadecola","year":"2011","unstructured":"Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med. 2011;17:796\u2013808.","journal-title":"Nat Med"},{"key":"4643_CR10","doi-asserted-by":"publisher","first-page":"2026","DOI":"10.1080\/15548627.2023.2167689","volume":"19","author":"N Hegdekar","year":"2023","unstructured":"Hegdekar N, Sarkar C, Bustos S, Ritzel RM, Hanscom M, Ravishankar P, Philkana D, Wu J, Loane DJ, Lipinski MM. Inhibition of autophagy in microglia and macrophages exacerbates innate immune responses and worsens brain injury outcomes. Autophagy. 2023;19:2026\u201344.","journal-title":"Autophagy"},{"key":"4643_CR11","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1007\/s00281-022-00943-7","volume":"44","author":"JH DeLong","year":"2022","unstructured":"DeLong JH, Ohashi SN, O\u2019Connor KC, Sansing LH. Inflammatory Responses After Ischemic Stroke. Semin Immunopathol. 2022;44:625\u201348.","journal-title":"Semin Immunopathol"},{"key":"4643_CR12","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1111\/bph.13139","volume":"173","author":"R Orihuela","year":"2016","unstructured":"Orihuela R, McPherson CA, Harry GJ. Microglial M1\/M2 polarization and metabolic states. Br J Pharmacol. 2016;173:649\u201365.","journal-title":"Br J Pharmacol"},{"key":"4643_CR13","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1186\/s12951-024-02560-y","volume":"22","author":"Y Wang","year":"2024","unstructured":"Wang Y, Liu Z, Li L, Zhang Z, Zhang K, Chu M, Liu Y, Mao X, Wu D, Xu D, Zhao J. Anti-ferroptosis exosomes engineered for targeting M2 microglia to improve neurological function in ischemic stroke. J Nanobiotechnol. 2024;22:291.","journal-title":"J Nanobiotechnol"},{"key":"4643_CR14","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/j.ymthe.2019.09.004","volume":"28","author":"S Kobashi","year":"2020","unstructured":"Kobashi S, Terashima T, Katagi M, Nakae Y, Okano J, Suzuki Y, Urushitani M, Kojima H. Transplantation of M2-Deviated Microglia Promotes Recovery of Motor Function after Spinal Cord Injury in Mice. Mol Ther. 2020;28:254\u201365.","journal-title":"Mol Ther"},{"key":"4643_CR15","doi-asserted-by":"publisher","first-page":"2686","DOI":"10.1016\/j.neuron.2024.05.023","volume":"112","author":"JP Chadarevian","year":"2024","unstructured":"Chadarevian JP, Hasselmann J, Lahian A, Capocchi JK, Escobar A, Lim TE, Le L, Tu C, Nguyen J, Kiani Shabestari S, et al. Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy. Neuron. 2024;112:2686\u2013e27072688.","journal-title":"Neuron"},{"key":"4643_CR16","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1038\/cr.2014.135","volume":"25","author":"L Ma","year":"2015","unstructured":"Ma L, Li Y, Peng J, Wu D, Zhao X, Cui Y, Chen L, Yan X, Du Y, Yu L. Discovery of the migrasome, an organelle mediating release of cytoplasmic contents during cell migration. Cell Res. 2015;25:24\u201338.","journal-title":"Cell Res"},{"key":"4643_CR17","doi-asserted-by":"publisher","first-page":"e11683","DOI":"10.1002\/advs.202511683","volume":"13","author":"QT Chen","year":"2026","unstructured":"Chen QT, Huang QL, Han MZ, Hong XH, Feng DY, Yao LM, Hong WB, Chen Y, Huang YY, Chen HZ, Wu Q. ITM2B Truncation Promotes Migrasome Formation to Accelerate Renal Cell Carcinoma Growth. Adv Sci (Weinh). 2026;13:e11683.","journal-title":"Adv Sci (Weinh)"},{"key":"4643_CR18","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1186\/s12964-023-01121-4","volume":"21","author":"Y Jiang","year":"2023","unstructured":"Jiang Y, Liu X, Ye J, Ma Y, Mao J, Feng D, Wang X. Migrasomes, a new mode of intercellular communication. Cell Commun Signal. 2023;21:105.","journal-title":"Cell Commun Signal"},{"key":"4643_CR19","doi-asserted-by":"publisher","first-page":"2039","DOI":"10.1038\/s43587-025-00956-5","volume":"5","author":"M Hu","year":"2025","unstructured":"Hu M, Kang X, Liu Z, Wang S, Liu S, Li C, Lu D, Qin Q, Liu Y, Yi H, et al. Senescent-like border-associated macrophages regulate cognitive aging via migrasome-mediated induction of paracrine senescence in microglia. Nat Aging. 2025;5:2039\u201354.","journal-title":"Nat Aging"},{"key":"4643_CR20","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1186\/s40364-026-00904-4","volume":"14","author":"Y Zhao","year":"2026","unstructured":"Zhao Y, Tang S, Zhou J, Luo Y, Duan L. Migrasomes: a journey from biogenesis to multifaceted roles in health and disease. Biomark Res. 2026;14:31.","journal-title":"Biomark Res"},{"key":"4643_CR21","doi-asserted-by":"crossref","unstructured":"Sheng D, Chen X, Shi J, Tang H. The mechanisms and functions of mitochondria-encapsulating extracellular vesicles. Sci China Life Sci. 2026;69(4):1091\u2013100.","DOI":"10.1007\/s11427-024-2905-5"},{"key":"4643_CR22","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1186\/s12951-025-03362-6","volume":"23","author":"Q Zhang","year":"2025","unstructured":"Zhang Q, Su J, Li Z, Han S, Wang C, Sun Z. Migrasomes as intercellular messengers: potential in the pathological mechanism, diagnosis and treatment of clinical diseases. J Nanobiotechnol. 2025;23:302.","journal-title":"J Nanobiotechnol"},{"key":"4643_CR23","doi-asserted-by":"publisher","first-page":"2910","DOI":"10.7150\/thno.30879","volume":"9","author":"Y Song","year":"2019","unstructured":"Song Y, Li Z, He T, Qu M, Jiang L, Li W, Shi X, Pan J, Zhang L, Wang Y, et al. M2 microglia-derived exosomes protect the mouse brain from ischemia-reperfusion injury via exosomal miR-124. Theranostics. 2019;9:2910\u201323.","journal-title":"Theranostics"},{"key":"4643_CR24","doi-asserted-by":"publisher","first-page":"3553","DOI":"10.7150\/thno.68895","volume":"12","author":"Y Li","year":"2022","unstructured":"Li Y, Liu Z, Song Y, Pan JJ, Jiang Y, Shi X, Liu C, Ma Y, Luo L, Mamtilahun M, et al. M2 microglia-derived extracellular vesicles promote white matter repair and functional recovery via miR-23a-5p after cerebral ischemia in mice. Theranostics. 2022;12:3553\u201373.","journal-title":"Theranostics"},{"key":"4643_CR25","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1007\/s11481-023-10071-0","volume":"18","author":"TT Li","year":"2023","unstructured":"Li TT, Zhao DM, Wei YT, Li JB, Li XF, Wan Q, Zhang X, Liu XN, Yang WC, Li WZ. Effect and Mechanism of Sodium Butyrate on Neuronal Recovery and Prognosis in Diabetic Stroke. J Neuroimmune Pharmacol. 2023;18:366\u201382.","journal-title":"J Neuroimmune Pharmacol"},{"key":"4643_CR26","doi-asserted-by":"publisher","first-page":"e2307556","DOI":"10.1002\/advs.202307556","volume":"11","author":"X Li","year":"2024","unstructured":"Li X, Sr., Liu W, Jiang G, Lian J, Zhong Y, Zhou J, Li H, Xu X, Liu Y, Cao C, et al. Celastrol Ameliorates Neuronal Mitochondrial Dysfunction Induced by Intracerebral Hemorrhage via Targeting cAMP-Activated Exchange Protein-1. Adv Sci (Weinh). 2024;11:e2307556.","journal-title":"Adv Sci (Weinh)"},{"key":"4643_CR27","doi-asserted-by":"publisher","first-page":"1670","DOI":"10.1038\/s41401-021-00803-4","volume":"43","author":"HJ Wang","year":"2022","unstructured":"Wang HJ, Ran HF, Yin Y, Xu XG, Jiang BX, Yu SQ, Chen YJ, Ren HJ, Feng S, Zhang JF, et al. Catalpol improves impaired neurovascular unit in ischemic stroke rats via enhancing VEGF-PI3K\/AKT and VEGF-MEK1\/2\/ERK1\/2 signaling. Acta Pharmacol Sin. 2022;43:1670\u201385.","journal-title":"Acta Pharmacol Sin"},{"key":"4643_CR28","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1111\/cns.13561","volume":"27","author":"L Wang","year":"2021","unstructured":"Wang L, Xiong X, Zhang L, Shen J. Neurovascular Unit: A critical role in ischemic stroke. CNS Neurosci Ther. 2021;27:7\u201316.","journal-title":"CNS Neurosci Ther"},{"key":"4643_CR29","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1161\/STROKEAHA.122.036946","volume":"53","author":"E Candelario-Jalil","year":"2022","unstructured":"Candelario-Jalil E, Dijkhuizen RM, Magnus T. Neuroinflammation, Stroke, Blood-Brain Barrier Dysfunction, and Imaging Modalities. Stroke. 2022;53:1473\u201386.","journal-title":"Stroke"},{"key":"4643_CR30","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1038\/s41420-023-01673-x","volume":"9","author":"X Zhang","year":"2023","unstructured":"Zhang X, Yao L, Meng Y, Li B, Yang Y, Gao F. Migrasome: a new functional extracellular vesicle. Cell Death Discov. 2023;9:381.","journal-title":"Cell Death Discov"},{"key":"4643_CR31","doi-asserted-by":"publisher","first-page":"112389","DOI":"10.1016\/j.cellsig.2026.112389","volume":"141","author":"S Zhang","year":"2026","unstructured":"Zhang S, Yang Y, Zhang T, Pan Y, Xu Q, L\u00fc P. Mechanisms and therapeutic potential of migrasomes in neurological disorders. Cell Signal. 2026;141:112389.","journal-title":"Cell Signal"},{"key":"4643_CR32","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1038\/s41422-024-00992-7","volume":"34","author":"H Jiao","year":"2024","unstructured":"Jiao H, Li X, Li Y, Guo Y, Hu X, Sho T, Luo Y, Wang J, Cao H, Du W, et al. Localized, highly efficient secretion of signaling proteins by migrasomes. Cell Res. 2024;34:572\u201385.","journal-title":"Cell Res"},{"key":"4643_CR33","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1002\/glia.24501","volume":"72","author":"AM Planas","year":"2024","unstructured":"Planas AM. Role of microglia in stroke. Glia. 2024;72:1016\u201353.","journal-title":"Glia"},{"key":"4643_CR34","doi-asserted-by":"publisher","first-page":"115772","DOI":"10.1016\/j.bcp.2023.115772","volume":"216","author":"X Dou","year":"2023","unstructured":"Dou X, Ji W, Dai M, Sun S, Chen R, Yang J, Long J, Ge Y, Lin Y. Spatial and temporal mapping of neuron-microglia interaction modes in acute ischemic stroke. Biochem Pharmacol. 2023;216:115772.","journal-title":"Biochem Pharmacol"},{"key":"4643_CR35","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1186\/s12967-024-05492-1","volume":"22","author":"P Li","year":"2024","unstructured":"Li P, Zhao J, Ma Y, Wang L, Liang S, Fan F, Wei T, Feng L, Hu X, Hu Y, et al. Transplantation of miR-145a-5p modified M2 type microglia promotes the tissue repair of spinal cord injury in mice. J Transl Med. 2024;22:724.","journal-title":"J Transl Med"},{"key":"4643_CR36","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s12951-023-02255-w","volume":"22","author":"P Guan","year":"2024","unstructured":"Guan P, Fan L, Zhu Z, Yang Q, Kang X, Li J, Zhang Z, Liu S, Liu C, Wang X, et al. M2 microglia-derived exosome-loaded electroconductive hydrogel for enhancing neurological recovery after spinal cord injury. J Nanobiotechnol. 2024;22:8.","journal-title":"J Nanobiotechnol"},{"key":"4643_CR37","doi-asserted-by":"publisher","first-page":"2629","DOI":"10.1161\/STROKEAHA.122.041611","volume":"54","author":"Y Song","year":"2023","unstructured":"Song Y, Shi R, Liu Y, Cui F, Han L, Wang C, Chen T, Li Z, Zhang Z, Tang Y, et al. M2 Microglia Extracellular Vesicle miR-124 Regulates Neural Stem Cell Differentiation in Ischemic Stroke via AAK1\/NOTCH. Stroke. 2023;54:2629\u201339.","journal-title":"Stroke"},{"key":"4643_CR38","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/j.tcb.2024.05.003","volume":"35","author":"D Jiang","year":"2025","unstructured":"Jiang D, He J, Yu L. The migrasome, an organelle for cell-cell communication. Trends Cell Biol. 2025;35:205\u201316.","journal-title":"Trends Cell Biol"},{"key":"4643_CR39","doi-asserted-by":"publisher","first-page":"104349","DOI":"10.1016\/j.phrs.2019.104349","volume":"147","author":"W Eldahshan","year":"2019","unstructured":"Eldahshan W, Fagan SC, Ergul A. Inflammation within the neurovascular unit: Focus on microglia for stroke injury and recovery. Pharmacol Res. 2019;147:104349.","journal-title":"Pharmacol Res"},{"key":"4643_CR40","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1186\/s12974-021-02309-6","volume":"18","author":"SC Woodburn","year":"2021","unstructured":"Woodburn SC, Bollinger JL, Wohleb ES. The semantics of microglia activation: neuroinflammation, homeostasis, and stress. J Neuroinflammation. 2021;18:258.","journal-title":"J Neuroinflammation"},{"key":"4643_CR41","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1186\/1742-2094-11-98","volume":"11","author":"JD Cherry","year":"2014","unstructured":"Cherry JD, Olschowka JA, O\u2019Banion MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation. 2014;11:98.","journal-title":"J Neuroinflammation"},{"key":"4643_CR42","doi-asserted-by":"publisher","first-page":"123456","DOI":"10.1016\/j.ijpharm.2023.123456","volume":"646","author":"I Jarak","year":"2023","unstructured":"Jarak I, Isabel Santos A, Helena Pinto A, Domingues C, Silva I, Melo R, Veiga F, Figueiras A. Colorectal cancer cell exosome and cytoplasmic membrane for homotypic delivery of therapeutic molecules. Int J Pharm. 2023;646:123456.","journal-title":"Int J Pharm"},{"key":"4643_CR43","doi-asserted-by":"publisher","first-page":"115271","DOI":"10.1016\/j.colsurfb.2025.115271","volume":"258","author":"L Zhang","year":"2026","unstructured":"Zhang L, Hu R, Zhang J, Zhang H. Dual-targeted exosome nanoplatform co-delivering doxorubicin and Fuzi Lizhong Tang bioactives for synergistic DLBCL therapy and chemotherapy-induced diarrhea management. Colloids Surf B Biointerfaces. 2026;258:115271.","journal-title":"Colloids Surf B Biointerfaces"},{"key":"4643_CR44","first-page":"541","volume":"52","author":"JC Zuo","year":"2025","unstructured":"Zuo JC, Liang J, Hu N, Yao B, Zhang QJ, Zeng XL, Zhang LJ, Zhang X, Chang ZH, Chen C, et al. Hypoxia preconditioned MSC exosomes attenuate high-altitude cerebral edema via the miR-125a-5p\/RTEF-1 axis to protect vascular endothelial cells. Bioact Mater. 2025;52:541\u201363.","journal-title":"Bioact Mater"},{"key":"4643_CR45","doi-asserted-by":"publisher","first-page":"102160","DOI":"10.1016\/j.arr.2023.102160","volume":"93","author":"Y Long","year":"2024","unstructured":"Long Y, Li XQ, Deng J, Ye QB, Li D, Ma Y, Wu YY, Hu Y, He XF, Wen J, et al. Modulating the polarization phenotype of microglia - A valuable strategy for central nervous system diseases. Ageing Res Rev. 2024;93:102160.","journal-title":"Ageing Res Rev"},{"key":"4643_CR46","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1186\/s13287-022-03168-5","volume":"13","author":"N Honda","year":"2022","unstructured":"Honda N, Watanabe Y, Tokuoka Y, Hanajima R. Roles of microglia\/macrophage and antibody in cell sheet transplantation in the central nervous system. Stem Cell Res Ther. 2022;13:470.","journal-title":"Stem Cell Res Ther"},{"key":"4643_CR47","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1042\/BST20130253","volume":"42","author":"OL Roberts","year":"2014","unstructured":"Roberts OL, Dart C. cAMP signalling in the vasculature: the role of Epac (exchange protein directly activated by cAMP). Biochem Soc Trans. 2014;42:89\u201397.","journal-title":"Biochem Soc Trans"},{"key":"4643_CR48","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1128\/MCB.25.1.136-146.2005","volume":"25","author":"S Fukuhara","year":"2005","unstructured":"Fukuhara S, Sakurai A, Sano H, Yamagishi A, Somekawa S, Takakura N, Saito Y, Kangawa K, Mochizuki N. Cyclic AMP potentiates vascular endothelial cadherin-mediated cell-cell contact to enhance endothelial barrier function through an Epac-Rap1 signaling pathway. Mol Cell Biol. 2005;25:136\u201346.","journal-title":"Mol Cell Biol"},{"key":"4643_CR49","doi-asserted-by":"publisher","first-page":"2591","DOI":"10.1097\/00001756-200008030-00048","volume":"11","author":"C Corsi","year":"2000","unstructured":"Corsi C, Melani A, Bianchi L, Pedata F. Striatal A2A adenosine receptor antagonism differentially modifies striatal glutamate outflow in vivo in young and aged rats. NeuroReport. 2000;11:2591\u20135.","journal-title":"NeuroReport"},{"key":"4643_CR50","doi-asserted-by":"publisher","first-page":"116775","DOI":"10.1016\/j.jns.2020.116775","volume":"413","author":"M Xin","year":"2020","unstructured":"Xin M, Feng J, Hao Y, You J, Wang X, Yin X, Shang P, Ma D. Cyclic adenosine monophosphate in acute ischemic stroke: some to update, more to explore. J Neurol Sci. 2020;413:116775.","journal-title":"J Neurol Sci"},{"key":"4643_CR51","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.brainres.2014.10.059","volume":"1594","author":"EA Newell","year":"2015","unstructured":"Newell EA, Exo JL, Verrier JD, Jackson TC, Gillespie DG, Janesko-Feldman K, Kochanek PM, Jackson EK. 2\u2019,3\u2019-cAMP, 3\u2019-AMP, 2\u2019-AMP and adenosine inhibit TNF-\u03b1 and CXCL10 production from activated primary murine microglia via A2A receptors. Brain Res. 2015;1594:27\u201335.","journal-title":"Brain Res"},{"key":"4643_CR52","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s12974-021-02078-2","volume":"18","author":"S Yu","year":"2021","unstructured":"Yu S, Doycheva DM, Gamdzyk M, Yang Y, Lenahan C, Li G, Li D, Lian L, Tang J, Lu J, Zhang JH. Activation of MC1R with BMS-470539 attenuates neuroinflammation via cAMP\/PKA\/Nurr1 pathway after neonatal hypoxic-ischemic brain injury in rats. J Neuroinflammation. 2021;18:26.","journal-title":"J Neuroinflammation"},{"key":"4643_CR53","doi-asserted-by":"publisher","first-page":"110348","DOI":"10.1016\/j.cellsig.2022.110348","volume":"95","author":"A Bhadra","year":"2022","unstructured":"Bhadra A, Scruggs AK, Leavesley SJ, Annamdevula N, George AH, Britain AL, Francis CM, Knighten JM, Rich TC, Bauer NN. Extracellular vesicle-induced cyclic AMP signaling. Cell Signal. 2022;95:110348.","journal-title":"Cell Signal"},{"key":"4643_CR54","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1186\/s12967-023-04198-0","volume":"21","author":"S Hu","year":"2023","unstructured":"Hu S, Chen B, Zhou J, Liu F, Mao T, Pathak JL, Watanabe N, Li J. Dental pulp stem cell-derived exosomes revitalize salivary gland epithelial cell function in NOD mice via the GPER-mediated cAMP\/PKA\/CREB signaling pathway. J Transl Med. 2023;21:361.","journal-title":"J Transl Med"},{"key":"4643_CR55","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1091\/mbc.e09-07-0580","volume":"21","author":"K Noda","year":"2010","unstructured":"Noda K, Zhang J, Fukuhara S, Kunimoto S, Yoshimura M, Mochizuki N. Vascular endothelial-cadherin stabilizes at cell-cell junctions by anchoring to circumferential actin bundles through alpha- and beta-catenins in cyclic AMP-Epac-Rap1 signal-activated endothelial cells. Mol Biol Cell. 2010;21:584\u201396.","journal-title":"Mol Biol Cell"},{"key":"4643_CR56","doi-asserted-by":"publisher","first-page":"e1339768","DOI":"10.1080\/21688370.2017.1339768","volume":"5","author":"CJ Ramos","year":"2017","unstructured":"Ramos CJ, Antonetti DA. The role of small GTPases and EPAC-Rap signaling in the regulation of the blood-brain and blood-retinal barriers. Tissue Barriers. 2017;5:e1339768.","journal-title":"Tissue Barriers"},{"key":"4643_CR57","doi-asserted-by":"crossref","unstructured":"Wehbe N, Slika H, Mesmar J, Nasser SA, Pintus G, Baydoun S, Badran A, Kobeissy F, Eid AH, Baydoun E. The role of epac in cancer progression. Int J Mol Sci. 2020;21(18):6489.","DOI":"10.3390\/ijms21186489"},{"key":"4643_CR58","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1124\/pr.110.003707","volume":"65","author":"M Schmidt","year":"2013","unstructured":"Schmidt M, Dekker FJ, Maarsingh H. Exchange protein directly activated by cAMP (epac): a multidomain cAMP mediator in the regulation of diverse biological functions. Pharmacol Rev. 2013;65:670\u2013709.","journal-title":"Pharmacol Rev"},{"key":"4643_CR59","doi-asserted-by":"crossref","unstructured":"Robichaux WG 3rd, Cheng X. Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development. Physiol Rev. 2018;98:919\u20131053.","DOI":"10.1152\/physrev.00025.2017"},{"key":"4643_CR60","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1186\/s40168-022-01366-0","volume":"10","author":"PD Virwani","year":"2022","unstructured":"Virwani PD, Cai L, Yeung PKK, Qian G, Chen Y, Zhou L, Wong JWH, Wang Y, Ho JWK, Lau KK, et al. Deficiency of exchange protein directly activated by cAMP (EPAC)-1 in mice augments glucose intolerance, inflammation, and gut dysbiosis associated with Western diet. Microbiome. 2022;10:187.","journal-title":"Microbiome"},{"key":"4643_CR61","doi-asserted-by":"publisher","first-page":"111488","DOI":"10.1016\/j.biopha.2021.111488","volume":"139","author":"BM El-Mokadem","year":"2021","unstructured":"El-Mokadem BM, El-Abhar HS, Abdallah DM, Awad AS, Soubh AA. Epac-1\/Rap-1 signaling pathway orchestrates the reno-therapeutic effect of ticagrelor against renal ischemia\/reperfusion model. Biomed Pharmacother. 2021;139:111488.","journal-title":"Biomed Pharmacother"},{"key":"4643_CR62","doi-asserted-by":"publisher","first-page":"110014","DOI":"10.1016\/j.intimp.2023.110014","volume":"117","author":"X Sun","year":"2023","unstructured":"Sun X, Wang Y, Zhao Y, Xu X, Lu W, Li Y, Bian F, Xiang L, Zhou L. Activation of the Epac\/Rap1 signaling pathway alleviates blood-brain barrier disruption and brain damage following cerebral ischemia\/reperfusion injury. Int Immunopharmacol. 2023;117:110014.","journal-title":"Int Immunopharmacol"},{"key":"4643_CR63","doi-asserted-by":"publisher","first-page":"1703951","DOI":"10.3389\/fnins.2025.1703951","volume":"19","author":"J Li","year":"2025","unstructured":"Li J, He J, Gao K, Zou Y. Neuroprotective effect of resveratrol on Epac-1\/Rap-1 signaling pathway in ischemic stroke rats. Front Neurosci. 2025;19:1703951.","journal-title":"Front Neurosci"},{"key":"4643_CR64","doi-asserted-by":"publisher","first-page":"112299","DOI":"10.1016\/j.cellsig.2025.112299","volume":"139","author":"Y Wang","year":"2026","unstructured":"Wang Y, Lou J, Dai R, Chen L, Wang Y, Wang Y, Ling X, Jiang X, Cai F. Far-infrared irradiation suppresses pyroptosis in ischemic flaps through TRPV3-mediated activation of the A2AR\/EPAC1\/Rap1 signaling pathway. Cell Signal. 2026;139:112299.","journal-title":"Cell Signal"},{"key":"4643_CR65","doi-asserted-by":"publisher","first-page":"115483","DOI":"10.1016\/j.intimp.2025.115483","volume":"165","author":"A Wei","year":"2025","unstructured":"Wei A, Liu B, Li Y, Dong K, Zhao Y, Wang X, Sun Z, Xie F, Qian L. Rap1a regulates CUMS-induced neuroinflammation and cognitive dysfunction and emotional abnormalities in mice. Int Immunopharmacol. 2025;165:115483.","journal-title":"Int Immunopharmacol"},{"key":"4643_CR66","doi-asserted-by":"publisher","first-page":"115244","DOI":"10.1016\/j.jep.2022.115244","volume":"293","author":"J Shang","year":"2022","unstructured":"Shang J, Li Q, Jiang T, Bi L, Lu Y, Jiao J, Song Q, Yan M, Shabuerjiang L, Wang J, Liu X. Systems pharmacology, proteomics and in vivo studies identification of mechanisms of cerebral ischemia injury amelioration by Huanglian Jiedu Decoction. J Ethnopharmacol. 2022;293:115244.","journal-title":"J Ethnopharmacol"},{"key":"4643_CR67","doi-asserted-by":"publisher","first-page":"1366","DOI":"10.2337\/db13-1412","volume":"63","author":"L Xiao","year":"2014","unstructured":"Xiao L, Zhu X, Yang S, Liu F, Zhou Z, Zhan M, Xie P, Zhang D, Li J, Song P, et al. Rap1 ameliorates renal tubular injury in diabetic nephropathy. Diabetes. 2014;63:1366\u201380.","journal-title":"Diabetes"},{"key":"4643_CR68","doi-asserted-by":"crossref","unstructured":"Wang Y, Hu J, Zhu Q, Wang S, Yu S. Emerging potential of ras-proximate-1 (Rap1) in mediating neurodegenerative diseases. Curr Neuropharmacol. 2025.","DOI":"10.2174\/011570159X440842251020104840"},{"key":"4643_CR69","doi-asserted-by":"publisher","first-page":"4710","DOI":"10.7150\/thno.51739","volume":"11","author":"Y Cai","year":"2021","unstructured":"Cai Y, Liu H, Song E, Wang L, Xu J, He Y, Zhang D, Zhang L, Cheng KK, Jin L, et al. Deficiency of telomere-associated repressor activator protein 1 precipitates cardiac aging in mice via p53\/PPAR\u03b1 signaling. Theranostics. 2021;11:4710\u201327.","journal-title":"Theranostics"},{"key":"4643_CR70","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1016\/j.immuni.2015.02.005","volume":"42","author":"AK Jha","year":"2015","unstructured":"Jha AK, Huang SC, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, Chmielewski K, Stewart KM, Ashall J, Everts B, et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity. 2015;42:419\u201330.","journal-title":"Immunity"},{"key":"4643_CR71","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1186\/s12951-023-02114-8","volume":"21","author":"P Li","year":"2023","unstructured":"Li P, Yin R, Chen Y, Chang J, Yang L, Liu X, Xu H, Zhang X, Wang S, Han Q, Wei J. Engineered extracellular vesicles for ischemic stroke: a systematic review and meta-analysis of preclinical studies. J Nanobiotechnol. 2023;21:396.","journal-title":"J Nanobiotechnol"},{"key":"4643_CR72","doi-asserted-by":"publisher","first-page":"e70155","DOI":"10.1111\/jnc.70155","volume":"169","author":"VL de Rezende","year":"2025","unstructured":"de Rezende VL, Mathias K, de Aguiar da Costa M, Gon\u00e7alves CL, Barichello T, Petronilho F. The Role of Extracellular Vesicles in Brain-Peripheral Communication Following Ischemic Stroke: Implications for Neural Repair and Regeneration. J Neurochem. 2025;169:e70155.","journal-title":"J Neurochem"},{"key":"4643_CR73","doi-asserted-by":"publisher","first-page":"112999","DOI":"10.1016\/j.colsurfb.2022.112999","volume":"221","author":"MI Teixeira","year":"2023","unstructured":"Teixeira MI, Lopes CM, Amaral MH, Costa PC. Surface-modified lipid nanocarriers for crossing the blood-brain barrier (BBB): A current overview of active targeting in brain diseases. Colloids Surf B Biointerfaces. 2023;221:112999.","journal-title":"Colloids Surf B Biointerfaces"},{"key":"4643_CR74","doi-asserted-by":"publisher","first-page":"20348","DOI":"10.1021\/acsami.7b02303","volume":"9","author":"S Ruan","year":"2017","unstructured":"Ruan S, Xiao W, Hu C, Zhang H, Rao J, Wang S, Wang X, He Q, Gao H. Ligand-Mediated and Enzyme-Directed Precise Targeting and Retention for the Enhanced Treatment of Glioblastoma. ACS Appl Mater Interfaces. 2017;9:20348\u201360.","journal-title":"ACS Appl Mater Interfaces"},{"key":"4643_CR75","doi-asserted-by":"crossref","unstructured":"Cui J, Wang X, Li J, Zhu A, Du Y, Zeng W, Guo Y, Di L, Wang R. Immune exosomes loading self-assembled nanomicelles traverse the blood-brain barrier for chemo-immunotherapy against glioblastoma. ACS Nano. 2023.","DOI":"10.1021\/acsnano.2c10219"},{"key":"4643_CR76","doi-asserted-by":"publisher","first-page":"121949","DOI":"10.1016\/j.biomaterials.2022.121949","volume":"293","author":"FU Rehman","year":"2023","unstructured":"Rehman FU, Liu Y, Zheng M, Shi B. Exosomes based strategies for brain drug delivery. Biomaterials. 2023;293:121949.","journal-title":"Biomaterials"}],"container-title":["Journal of Nanobiotechnology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12951-026-04643-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12951-026-04643-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12951-026-04643-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T04:02:52Z","timestamp":1786334572000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12951-026-04643-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,4]]},"references-count":76,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4643"],"URL":"https:\/\/doi.org\/10.1186\/s12951-026-04643-4","relation":{},"ISSN":["1477-3155"],"issn-type":[{"value":"1477-3155","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,4]]},"assertion":[{"value":"1 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All animal experiments were approved by the Animal Experiment Ethics Committee of Sun Yat-sen University (SYSU-IACUC-2025-002457) in accordance with the National Institutes of Health guidelines.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"737"}}