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Small interfering RNAs (siRNAs) targeting TDP-43 offer potential therapeutic strategies for these diseases. However, efficient and safe delivery of siRNAs to the CNS remains a challenge.<\/jats:p>\n                  <jats:p>Here, we present a synthetic biology-based approach that leverages endogenous small RNA processing machinery to self-assemble siRNA-encapsulating small extracellular vesicles and uses the natural circulatory system of the host to transport siRNAs. Specifically, we engineered liver cells to express and package TDP-43-targeting siRNAs into rabies virus glycoprotein-tagged small extracellular vesicles, which are released into the circulation and cross the blood\u2013brain barrier to deliver siRNAs to the CNS.<\/jats:p>\n                  <jats:p>In a mouse model of TDP-43 pathology induced by stereotactic injection of mutant TDP-43 (M337V) virus, treatment with in vivo self-assembled TDP-43 siRNAs (IVSA-siR-TDP43) effectively reduced TDP-43 accumulation, leading to significant improvements in motor function and neuropathology. Additionally, an adeno-associated virus-based delivery system was used to produce IVSA-siR-TDP43, demonstrating sustained therapeutic effects in TDP-43-associated neurodegeneration. These findings highlight a novel, effective and minimally invasive gene therapy platform for addressing TDP-43 pathology in amyotrophic lateral sclerosis and frontotemporal lobar degeneration, offering a promising avenue for future clinical applications.<\/jats:p>","DOI":"10.1093\/brain\/awaf330","type":"journal-article","created":{"date-parts":[[2025,9,5]],"date-time":"2025-09-05T11:56:45Z","timestamp":1757073405000},"page":"828-839","source":"Crossref","is-referenced-by-count":3,"title":["<i>In vivo<\/i>\n                    self-assembled siRNAs ameliorate neurological pathology in TDP-43-associated neurodegenerative disease"],"prefix":"10.1093","volume":"149","author":[{"given":"Jianhao","family":"Wu","sequence":"first","affiliation":[{"name":"The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong 517000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University , Guangzhou, Guangdong 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwei","family":"Guo","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":"Jiaxi","family":"Wu","sequence":"additional","affiliation":[{"name":"The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong 517000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University , Guangzhou, Guangdong 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junzhu","family":"Song","sequence":"additional","affiliation":[{"name":"The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong 517000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University , Guangzhou, Guangdong 510632, 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":"Yingqi","family":"Lin","sequence":"additional","affiliation":[{"name":"The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong 517000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University , Guangzhou, Guangdong 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhui","family":"Huang","sequence":"additional","affiliation":[{"name":"The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong 517000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University , Guangzhou, Guangdong 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunxiang","family":"Shi","sequence":"additional","affiliation":[{"name":"The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong 517000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University , Guangzhou, Guangdong 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Li","sequence":"additional","affiliation":[{"name":"The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong 517000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University , Guangzhou, Guangdong 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caijuan","family":"Li","sequence":"additional","affiliation":[{"name":"The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong 517000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University , Guangzhou, Guangdong 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhi","family":"Chen","sequence":"additional","affiliation":[{"name":"The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong 517000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University , Guangzhou, Guangdong 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[{"name":"The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong 517000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University , Guangzhou, Guangdong 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiale","family":"Gao","sequence":"additional","affiliation":[{"name":"The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong 517000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University , Guangzhou, Guangdong 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Zhou","sequence":"additional","affiliation":[{"name":"The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong 517000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University , Guangzhou, Guangdong 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanpei","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong 517000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University , Guangzhou, Guangdong 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shihua","family":"Li","sequence":"additional","affiliation":[{"name":"The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong 517000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University , Guangzhou, Guangdong 510632, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9370-8838","authenticated-orcid":false,"given":"Xiao-Jiang","family":"Li","sequence":"additional","affiliation":[{"name":"The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong 517000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University , Guangzhou, 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University, Nanjing, Jiangsu 210023 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4889-1570","authenticated-orcid":false,"given":"Sen","family":"Yan","sequence":"additional","affiliation":[{"name":"The Fifth Affiliated Hospital (Heyuan Shenhe People's Hospital), Jinan University, Heyuan, Guangdong 517000, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Guangdong Provincial Key Laboratory of Non-human Primate Research, Guangdong-Hong Kong-Macau Institute of CNS Regeneration, Jinan University , Guangzhou, Guangdong 510632, China"},{"name":"Department of Neurology, Guangzhou Red Cross Hospital, Faculty of Medical Science, Jinan University , Guangzhou, Guangdong 510235 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