{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:01:06Z","timestamp":1790794866364,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The accumulation of mutant huntingtin (mHTT) aggregates drives the pathology of Huntington's disease (HD), yet therapies capable of distinguishing toxic species from wild\u2010type proteins remain elusive. Here, a synthetic gene circuit, termed ARAA, was engineered to couple the preferential recognition of aggregated polyQ species to the on\u2010demand activation of autophagy. Utilizing a repurposed bacterial NarX\u2013NarL system fused with a conformation\u2010sensitive intrabody, the circuit detects pathological polyQ conformers and triggers the transcriptional expression of the master autophagy regulator TFEB. To enable systemic application, the ARAA plasmid is encapsulated in CD98\u2010targeted immunoliposomes (LIP\u2010CD98) that facilitate efficient blood\u2010brain barrier crossing via receptor\u2010mediated transcytosis. In the R6\/2 HD mouse model, ARAA treatment significantly reduces mHTT burden, attenuates neuroinflammation, and rescues synaptic deficits. This closed\u2010loop intervention improves motor function and extends lifespan. Together, these findings provide proof\u2010of\u2010concept evidence that aggregate\u2010responsive regulation of autophagy can mitigate disease\u2010associated phenotypes in exon 1\u2010based HD models.<\/jats:p>","DOI":"10.1002\/advs.78018","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Huntingtin Aggregate\u2010Responsive Autophagy Gene Circuit Mitigates Disease Pathology in R6\/2 Mice"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7144-0471","authenticated-orcid":false,"given":"Jie","family":"Zhu","sequence":"first","affiliation":[{"name":"National Key Laboratory of Biopharmaceutical Preparation and Delivery Institute of Process Engineering Chinese Academy of Sciences  Beijing China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi\u2010xiu","family":"Xie","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Biopharmaceutical Preparation and Delivery Institute of Process Engineering Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology National Clinical Research Center for Obstetric &amp; Gynecologic Diseases Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Tian","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Biopharmaceutical Preparation and Delivery Institute of Process Engineering Chinese Academy of Sciences  Beijing China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao\u2010tian","family":"Wang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Biopharmaceutical Preparation and Delivery Institute of Process Engineering Chinese Academy of Sciences  Beijing China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010jie","family":"Wang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Biopharmaceutical Preparation and Delivery Institute of Process Engineering Chinese Academy of Sciences  Beijing China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao\u2010lin","family":"Yu","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Biopharmaceutical Preparation and Delivery Institute of Process Engineering Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gui\u2010feng","family":"Zhang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Biopharmaceutical Preparation and Delivery Institute of Process Engineering Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4297-4765","authenticated-orcid":false,"given":"Rui\u2010tian","family":"Liu","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Biopharmaceutical Preparation and Delivery Institute of Process Engineering Chinese Academy of Sciences  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,27]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2020.00754"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(22)00121\u20101"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2018.08.010"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2528"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1870\u201013.2014"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.07.017"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2012.14"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.05.009"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501507102"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.12.069"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2019.104637"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1204592"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010023\u201006154\u20108"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20140645"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.3791\/57506"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010023\u201040681\u20104"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1602\/neurorx.2.1.3"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1307152110"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(22)00120\u2010X"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010023\u201002566\u20103"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25073845"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.104320.3"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.11.024"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2008.12.064"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1042\/bst0310001"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41589\u2010019\u20100429\u20109"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.3233\/JHD\u20102012\u2010129004"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/mtm.2016.17"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2021.100853"},{"key":"e_1_2_10_31_1","unstructured":"K. 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