{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:26:08Z","timestamp":1790799968047,"version":"4.1.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"vor","delay-in-days":0,"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","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the death of both upper and lower motor neurons. Approximately 20% of familial ALS cases are associated with mutations in the superoxide dismutase type 1 (SOD1) gene. Developing a specific strategy to characteristically silence the pathogenic SOD1 gene remains a crucial goal amidst significant challenges.<\/jats:p>\n                  <jats:p>In this study, we developed a synthetic biology strategy to reprogramme the liver as a tissue chassis for the in vivo self-assembly of small extracellular vesicles (sEVs)-encapsulated SOD1-siRNA, aiming to target spinal neurons and silence mutant SOD1 specifically in Tg(SOD1G93A) transgenic mice. We designed a cytomegalovirus (CMV) promoter-directed synthetic construct to encode a SOD1-siRNA along with a neuron-targeting rabies virus glycoprotein (RVG) tagged on the sEV surface. Theoretically, upon liver uptake, this construct reprogrammes liver cells to generate and self-assemble SOD1-siRNAs into RVG-tagged sEVs. Subsequently, the sEV-encapsulated SOD1-siRNAs are transported via the endogenous sEV circulation and guided by the RVG tag to the spinal neurons.<\/jats:p>\n                  <jats:p>Experimental results illustrated that intravenous administration of this synthetic construct effectively facilitated in vivo self-assembly of SOD1-siRNAs into circulating sEVs. The functional delivery of SOD1-siRNAs to the spinal cord and cerebral cortex was confirmed through in vivo tracking of sEVs and sEV-encapsulated siRNAs. Treatment of Tg(SOD1G93A) transgenic mice with this construct significantly reduced mutant SOD1 protein levels in the spinal cord and cerebral cortex. Consequently, the characteristic symptoms of ALS, including decreased body weight, shortened lifespan, compromised motor function, muscle atrophy, neuroinflammation, motor neuron loss and neuromuscular junction degeneration, were substantially ameliorated by the synthetic construct. Furthermore, an AAV-based strategy was devised for the enduring self-assembly of sEV-encapsulated SOD1-siRNA, whereby a single injection led to substantial and sustained inhibition of mutant SOD1 and significant symptom amelioration in transgenic mice.<\/jats:p>\n                  <jats:p>Overall, this study established an effective and convenient therapeutic approach for mitigating muscle atrophy and denervation in animal model, presenting a promising solution for future ALS treatment.<\/jats:p>","DOI":"10.1093\/brain\/awaf291","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T11:40:13Z","timestamp":1754480413000},"page":"785-800","source":"Crossref","is-referenced-by-count":6,"title":["<i>In vivo<\/i>\n                    self-assembled SOD1-siRNAs mitigate muscle atrophy and denervation in amyotrophic lateral sclerosis"],"prefix":"10.1093","volume":"149","author":[{"given":"Jingwei","family":"Guo","sequence":"first","affiliation":[{"name":"Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, 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 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zou","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, 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 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Xu","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, 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 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieqiong","family":"Lei","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, 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 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yin","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, 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 ,","place":["China"]},{"name":"The Second People\u2019s Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University , Changzhou, Jiangsu 213003 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Botao","family":"Li","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, 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 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyu","family":"Fu","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, 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 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Mi","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, 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 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanbo","family":"Wang","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, 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 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University , Nanjing, Jiangsu 210029 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, 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 ,","place":["China"]},{"name":"Research Unit of Extracellular RNA, Chinese Academy of Medical Sciences , Nanjing, Jiangsu 210023 ,","place":["China"]},{"name":"Institute of Artificial Intelligence Biomedicine, Nanjing University , Nanjing, Jiangsu 210023 ,","place":["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, 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 ,","place":["China"]},{"name":"The Second People\u2019s Hospital of Changzhou, The Third Affiliated Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University , Changzhou, Jiangsu 213003 ,","place":["China"]},{"name":"Institute of Artificial Intelligence Biomedicine, Nanjing University , Nanjing, Jiangsu 210023 ,","place":["China"]},{"name":"Chemistry and Biomedicine Innovation Center (ChemBIC), Nanjing University , Nanjing, Jiangsu 210023 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"2026030512074080400_awaf291-B1","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1056\/NEJM200105313442207","article-title":"Amyotrophic lateral sclerosis","volume":"344","author":"Rowland","year":"2001","journal-title":"N Engl J 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