{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T03:16:56Z","timestamp":1793157416622,"version":"4.5.0"},"reference-count":65,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T00:00:00Z","timestamp":1639612800000},"content-version":"vor","delay-in-days":45,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32022015"],"award-info":[{"award-number":["32022015"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31871295"],"award-info":[{"award-number":["31871295"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013290","name":"National Key Research and Development Program of China, Stem Cell and Translational Research","doi-asserted-by":"crossref","award":["2017YFA0105104"],"award-info":[{"award-number":["2017YFA0105104"]}],"id":[{"id":"10.13039\/501100013290","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BE2016737"],"award-info":[{"award-number":["BE2016737"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Guangdong Provincial Science and Technology Plan Project","award":["2016B030230002"],"award-info":[{"award-number":["2016B030230002"]}]},{"name":"Guangdong Provincial Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases","award":["2017B030314103"],"award-info":[{"award-number":["2017B030314103"]}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["020814380162"],"award-info":[{"award-number":["020814380162"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,12,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Huntington\u2019s disease is an autosomal-dominant neurodegenerative disease caused by CAG expansion in exon 1 of the huntingtin (HTT) gene. Since mutant huntingtin (mHTT) protein is the root cause of Huntington\u2019s disease, oligonucleotide-based therapeutic approaches using small interfering RNAs (siRNAs) and antisense oligonucleotides designed to specifically silence mHTT may be novel therapeutic strategies for Huntington\u2019s disease. Unfortunately, the lack of an effective in vivo delivery system remains a major obstacle to realizing the full potential of oligonucleotide therapeutics, especially regarding the delivery of oligonucleotides to the cortex and striatum, the most severely affected brain regions in Huntington\u2019s disease.<\/jats:p>\n                  <jats:p>In this study, we present a synthetic biology strategy that integrates the naturally existing exosome-circulating system with artificial genetic circuits for self-assembly and delivery of mHTT-silencing siRNA to the cortex and striatum. We designed a cytomegalovirus promoter-directed genetic circuit encoding both a neuron-targeting rabies virus glycoprotein tag and an mHTT siRNA.<\/jats:p>\n                  <jats:p>After being taken up by mouse livers after intravenous injection, this circuit was able to reprogramme hepatocytes to transcribe and self-assemble mHTT siRNA into rabies virus glycoprotein-tagged exosomes. The mHTT siRNA was further delivered through the exosome-circulating system and guided by a rabies virus glycoprotein tag to the cortex and striatum. Consequently, in three mouse models of Huntington\u2019s disease treated with this circuit, the levels of mHTT protein and toxic aggregates were successfully reduced in the cortex and striatum, therefore ameliorating behavioural deficits and striatal and cortical neuropathologies.<\/jats:p>\n                  <jats:p>Overall, our findings establish a convenient, effective and safe strategy for self-assembly of siRNAs in vivo that may provide a significant therapeutic benefit for Huntington\u2019s disease.<\/jats:p>","DOI":"10.1093\/brain\/awab354","type":"journal-article","created":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T17:40:22Z","timestamp":1632418822000},"page":"3421-3435","source":"Crossref","is-referenced-by-count":96,"title":["Therapeutic reversal of Huntington\u2019s disease by\n                    <i>in vivo<\/i>\n                    self-assembled siRNAs"],"prefix":"10.1093","volume":"144","author":[{"given":"Li","family":"Zhang","sequence":"first","affiliation":[{"name":"Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, Chinese Academy of Medical Sciences Research Unit of Extracellular RNA, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tengteng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China"},{"name":"Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangyang","family":"Shan","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, Chinese Academy of Medical Sciences Research Unit of Extracellular RNA, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, Guangdong 510663, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Ni","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, Chinese Academy of Medical Sciences Research Unit of Extracellular RNA, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaorui","family":"Chen","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, Chinese Academy of Medical Sciences Research Unit of Extracellular RNA, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuting","family":"Hu","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, Chinese Academy of Medical Sciences Research Unit of Extracellular RNA, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lishan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongchao","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, Guangdong 510663, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalun","family":"Guan","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, Guangdong 510663, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfeng","family":"Gao","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, Guangdong 510663, China"},{"name":"School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, Guangdong 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingbang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, Guangdong 510663, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8425-2867","authenticated-orcid":false,"given":"Zhong","family":"Pei","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6756-7130","authenticated-orcid":false,"given":"Xi","family":"Chen","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, Chinese Academy of Medical Sciences Research Unit of Extracellular RNA, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, 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