Intranasal delivery of BDNF-loaded small extracellular vesicles for cerebral ischemia therapy

doi:10.1016/j.jconrel.2023.03.033

. 2023 May:357:1-19.

doi: 10.1016/j.jconrel.2023.03.033. Epub 2023 Mar 28.

Intranasal delivery of BDNF-loaded small extracellular vesicles for cerebral ischemia therapy

Xin Zhou¹, Xiaohui Deng², Mengfan Liu³, Meiting He³, Wenhui Long³, Zhibin Xu², Kun Zhang⁴, Tao Liu⁴, Kwok-Fai So⁵, Qing-Ling Fu⁶, Libing Zhou⁷

Affiliations

¹ Department of Neurology and Stroke Center, The First Affiliated Hospital & Clinical Neuroscience Institute of Jinan University, Guangzhou 510632, PR China; Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Jinan University), Ministry of Education, Guangzhou 510632, PR China.
² Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China.
³ Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Jinan University), Ministry of Education, Guangzhou 510632, PR China.
⁴ Department of Neurology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou 570311, Hainan, PR China.
⁵ Department of Neurology and Stroke Center, The First Affiliated Hospital & Clinical Neuroscience Institute of Jinan University, Guangzhou 510632, PR China; Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Jinan University), Ministry of Education, Guangzhou 510632, PR China; Co-innovation Center of Neuroregeneration, Nantong University, Jiangsu, PR China; Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao 266071, Shandong, PR China; Center for Exercise and Brain Science, School of Psychology, Shanghai University of Sport, Shanghai 200438, PR China.
⁶ Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China; Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China. Electronic address: fuqingl@mail.sysu.edu.cn.
⁷ Department of Neurology and Stroke Center, The First Affiliated Hospital & Clinical Neuroscience Institute of Jinan University, Guangzhou 510632, PR China; Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Jinan University), Ministry of Education, Guangzhou 510632, PR China; Department of Neurology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou 570311, Hainan, PR China; Co-innovation Center of Neuroregeneration, Nantong University, Jiangsu, PR China; Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao 266071, Shandong, PR China; Center for Exercise and Brain Science, School of Psychology, Shanghai University of Sport, Shanghai 200438, PR China. Electronic address: tlibingzh@jnu.edu.cn.

PMID: 36958402
DOI: 10.1016/j.jconrel.2023.03.033

Free article

Intranasal delivery of BDNF-loaded small extracellular vesicles for cerebral ischemia therapy

Xin Zhou et al. J Control Release. 2023 May.

Free article

. 2023 May:357:1-19.

doi: 10.1016/j.jconrel.2023.03.033. Epub 2023 Mar 28.

Authors

Xin Zhou¹, Xiaohui Deng², Mengfan Liu³, Meiting He³, Wenhui Long³, Zhibin Xu², Kun Zhang⁴, Tao Liu⁴, Kwok-Fai So⁵, Qing-Ling Fu⁶, Libing Zhou⁷

Affiliations

¹ Department of Neurology and Stroke Center, The First Affiliated Hospital & Clinical Neuroscience Institute of Jinan University, Guangzhou 510632, PR China; Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Jinan University), Ministry of Education, Guangzhou 510632, PR China.
² Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China.
³ Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Jinan University), Ministry of Education, Guangzhou 510632, PR China.
⁴ Department of Neurology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou 570311, Hainan, PR China.
⁵ Department of Neurology and Stroke Center, The First Affiliated Hospital & Clinical Neuroscience Institute of Jinan University, Guangzhou 510632, PR China; Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Jinan University), Ministry of Education, Guangzhou 510632, PR China; Co-innovation Center of Neuroregeneration, Nantong University, Jiangsu, PR China; Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao 266071, Shandong, PR China; Center for Exercise and Brain Science, School of Psychology, Shanghai University of Sport, Shanghai 200438, PR China.
⁶ Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China; Extracellular Vesicle Research and Clinical Translational Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, PR China. Electronic address: fuqingl@mail.sysu.edu.cn.
⁷ Department of Neurology and Stroke Center, The First Affiliated Hospital & Clinical Neuroscience Institute of Jinan University, Guangzhou 510632, PR China; Guangdong-Hongkong-Macau CNS Regeneration Institute of Jinan University, Key Laboratory of CNS Regeneration (Jinan University), Ministry of Education, Guangzhou 510632, PR China; Department of Neurology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou 570311, Hainan, PR China; Co-innovation Center of Neuroregeneration, Nantong University, Jiangsu, PR China; Neuroscience and Neurorehabilitation Institute, University of Health and Rehabilitation Sciences, Qingdao 266071, Shandong, PR China; Center for Exercise and Brain Science, School of Psychology, Shanghai University of Sport, Shanghai 200438, PR China. Electronic address: tlibingzh@jnu.edu.cn.

PMID: 36958402
DOI: 10.1016/j.jconrel.2023.03.033

Abstract

Mesenchymal stem cells (MSCs) have shown promise for the therapy of cerebral ischemia in animal studies and clinical trials, yet their clinical application still faces many challenges. Utilizing small extracellular vesicles (sEVs) may overcome these challenges. In the study, we overexpressed brain-derived neurotrophic factor (BDNF) in cultured MSCs and purified sEVs using anion exchange chromatography. In an ischemic stroke mouse model, sEVs selectively targeted the peri-infarct region after intranasal administration, and BDNF loading enhanced the efficacy of sEVs in improved functional behavior, neural repair indicated by infarct volume reduction, increased neurogenesis, angiogenesis, synaptic plasticity, and fiber preservation, as well as decreased inflammatory-cytokine expression and glial response. Intranasal administration of sEVs and BDNF-sEVs resulted in upregulation of neuroprotection-related genes and downregulation of inflammation-related genes, and BDNF-sEVs treatment activated the BDNF/TrkB signaling in the ischemic brain. Transcriptomic and proteomic analysis of sEVs and BDNF-sEVs disclosed abundant proteins and miRNAs involved in neuroprotection and anti-inflammation, and BDNF-sEVs showed different characteristics from sEVs. In conclusion, intranasal delivery of sEVs-loaded BDNF is a promising alternative strategy for the therapy of cerebral ischemia.

Keywords: Brain-derived neurotrophic factor; Intranasal delivery; Ischemic stroke; Mesenchymal stem cells; Small extracellular vesicles.

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Conflict of interest statement

Declaration of Competing Interest The authors have no conflict of interest.

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Intranasal delivery of BDNF-loaded small extracellular vesicles for cerebral ischemia therapy

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Intranasal delivery of BDNF-loaded small extracellular vesicles for cerebral ischemia therapy

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