{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T22:03:53Z","timestamp":1789509833825,"version":"build-2803163510"},"reference-count":53,"publisher":"Wiley","issue":"38","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82374212"],"award-info":[{"award-number":["82374212"]}],"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":["81673811"],"award-info":[{"award-number":["81673811"]}],"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":["81971446"],"award-info":[{"award-number":["81971446"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Wilson's disease (WD), as a typical disease of excessive Cu\n                    <jats:sup>2+<\/jats:sup>\n                    deposition, is characterized by disorders of copper metabolism in the brain and thereby damaging the reproductive system. Conventional interventions using copper chelators can temporarily reduce intracellular copper (in\u2010copper), but continuous re\u2010entry of extracellular copper (ex\u2010copper) into cells results in suboptimal therapy. Effective therapy requires multipronged copper metabolism management. Here, an orally administered, engineered Ganoderma\u2010derived extracellular vesicle (CZGE) is developed for synergistic in\/ex\u2010copper regulation. Specifically, CZGE is designed by co\u2010fusing Ganoderma\u2010derived extracellular vesicle (GEVs) and targeted nanomicelles containing zinc\u2010curcumin (Zn\u2010Cur) complex (ZCNs). CZGE, with\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010glucan\u2010enriched GEVs and kisspeptin\u201010\u2010modified ZCNs, can effectively penetrate intestinal and brain barriers after oral administration to target hypothalamic neurons.After internalization, Zn\u2010Cur released from CZGE replaces excess Cu\n                    <jats:sup>2+<\/jats:sup>\n                    to form copper\u2010curcumin (Cu\u2010Cur) and release Zn\n                    <jats:sup>2+<\/jats:sup>\n                    via ion exchange. Cu\u2010Cur reduces in\u2010copper and neuroinflammation via the Nrf2\/NLRP3 pathway, while Zn\n                    <jats:sup>2+<\/jats:sup>\n                    inhibits ex\u2010copper influx by activating zinc transporter 1. In WD mice, CZGE alleviates hypothalamic copper deposition, activates ERK1\/2 phosphorylation, and repairs reproductive dysfunction by modulating the hypothalamic\u2010pituitary\u2010testicular axis. It first reveals a targeted nanomedicine based on ion exchange that multipronged management in\u2010copper and ex\u2010copper, offering a promising therapeutic strategy for addressing WD with reproductive dysfunction.\n                  <\/jats:p>","DOI":"10.1002\/advs.202501689","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T14:21:13Z","timestamp":1752762073000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Oral Engineered Extracellular Vesicles Based on Ion Exchange Strategy for Multipronged Management of Wilson's Disease Complicated with Reproductive Dysfunction Therapy"],"prefix":"10.1002","volume":"12","author":[{"given":"Tingting","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Anhui University of Chinese Medicine  Hefei Anhui 230031 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wengui","family":"Lu","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application School of Pharmacy Anhui University of Chinese Medicine  Hefei Anhui 230012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifei","family":"Cheng","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application School of Pharmacy Anhui University of Chinese Medicine  Hefei Anhui 230012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luyao","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Anhui University of Chinese Medicine  Hefei Anhui 230031 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenzhen","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Anhui University of Chinese Medicine  Hefei Anhui 230031 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yike","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Anhui University of Chinese Medicine  Hefei Anhui 230031 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengyu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Anhui University of Chinese Medicine  Hefei Anhui 230031 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zehua","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Anhui University of Chinese Medicine  Hefei Anhui 230031 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"He","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Anhui University of Chinese Medicine  Hefei Anhui 230031 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengying","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Anhui University of Chinese Medicine  Hefei Anhui 230031 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limin","family":"Wu","sequence":"additional","affiliation":[{"name":"Center for Reproduction and Genetics The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China  Hefei Anhui 230001 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Wang","sequence":"additional","affiliation":[{"name":"Anhui Province Key Laboratory of Pharmaceutical Preparation Technology and Application School of Pharmacy Anhui University of Chinese Medicine  Hefei Anhui 230012 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5909-8523","authenticated-orcid":false,"given":"Hui","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Anhui University of Chinese Medicine  Hefei Anhui 230031 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,17]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31681"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jphotobiol.2021.112322"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsanm.1c03227"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21239259"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25094753"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2024.173603"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr300045n"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202310061"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/ic502957d"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41565-021-00931-2"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2024.07.009"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23169316"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.31635\/ccschem.023.202303514"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2023.e17468"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2404013121"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molstruc.2010.09.049"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2021-326123"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28141"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhazmat.2023.131719"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygcen.2019.113342"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/andr.13002"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2023.2200554"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0000000000001787"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12274-021-3864-3"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2020.1841953"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2021.06.029"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202312925"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202300601"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.carbpol.2023.120668"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodres.2019.108648"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rbmo.2020.12.012"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2013.03.012"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.8b00470"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-44852-9"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2305378120"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1155\/2021\/9265016"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2024.111060"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202215307"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c01231"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c01929"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature15514"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2016.02.019"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23010191"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2003.10.007"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1745"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202401570"},{"key":"e_1_2_8_47_1","first-page":"145","volume":"135","author":"Yoshida S.","year":"2019","journal-title":"Curr. Top. Dev. Biol."},{"key":"e_1_2_8_48_1","first-page":"115","volume":"60","author":"Bili\u0144ska B.","year":"1989","journal-title":"Cytobios"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/jemt.1060190205"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2010.08.019"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2024.155516"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.06.028"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-023-01365-6"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202501689","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.202501689","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202501689","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T19:31:54Z","timestamp":1773084714000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202501689"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,17]]},"references-count":53,"journal-issue":{"issue":"38","published-print":{"date-parts":[[2025,10]]}},"alternative-id":["10.1002\/advs.202501689"],"URL":"https:\/\/doi.org\/10.1002\/advs.202501689","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,17]]},"assertion":[{"value":"2025-01-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01689"}}