{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T23:51:39Z","timestamp":1769730699384,"version":"3.49.0"},"reference-count":45,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"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"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Metallothionein 3 (Mt3) is crucial for cellular homeostasis and neuroprotection, with accumulating evidence linking it to amyloid\u2010beta (A\u03b2) clearance by astrocytes. This study developed a CRISPR activator (CRISPRa) system using lipid nanoparticles to selectively upregulate Mt3 in astrocytes, aiming to enhance A\u03b2 endocytosis in an Alzheimer's disease (AD) mouse model. To directly assess the therapeutic potential of Mt3 activation in a specific brain region, stereotaxic injection is utilized to deliver the CRISPRa lipid nanocomplexes. This approach enabled precise in vivo brain delivery and Mt3 activation. The findings reveal that CRISPRa lipid nanocomplex\u2010mediated Mt3 upregulation significantly boosts A\u03b2 uptake by astrocytes, leading to a marked reduction in A\u03b2 plaque accumulation in AD mouse brains. These results highlight CRISPRa lipid nanocomplex\u2010mediated Mt3 targeting as a promising strategy to enhance endogenous A\u03b2 clearance, presenting a novel therapeutic avenue for AD.<\/jats:p>","DOI":"10.1002\/advs.202503725","type":"journal-article","created":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T03:34:06Z","timestamp":1765596846000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CRISPRa Lipid Nanocomplex\u2010Mediated Mt3 Targeting Enhances Astrocytic Endocytosis of Amyloid\u2010\u03b2 in an Alzheimer's Disease Mouse Model"],"prefix":"10.1002","volume":"13","author":[{"given":"Junhang","family":"Park","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Genetics College of Pharmacy Chungbuk National University  Cheongju 28160 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6479-3105","authenticated-orcid":false,"given":"Boyoung","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Genetics College of Pharmacy Chungbuk National University  Cheongju 28160 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minki","family":"Ha","sequence":"additional","affiliation":[{"name":"Center for Gene &amp; Cell Therapy Korea Research Institute of Bioscience and Biotechnology (KRIBB)  Chungcheongbuk\u2010do 28116 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moonsu","family":"Park","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Genetics College of Pharmacy Chungbuk National University  Cheongju 28160 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongji","family":"Ryu","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Genetics College of Pharmacy Chungbuk National University  Cheongju 28160 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyerin","family":"Yu","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Genetics College of Pharmacy Chungbuk National University  Cheongju 28160 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sungsoo","family":"Park","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine Jeonbuk National University  Iksan 54596 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoon\u2010Seok","family":"Roh","sequence":"additional","affiliation":[{"name":"College of Pharmacy Chungbuk National University  Osongsaengmyeong 1\u2010ro, Osong\u2010eup, Heungdeok\u2010gu Cheongju 28160 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Key\u2010Hwan","family":"Lim","sequence":"additional","affiliation":[{"name":"College of Pharmacy Chungbuk National University  Osongsaengmyeong 1\u2010ro, Osong\u2010eup, Heungdeok\u2010gu Cheongju 28160 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin Tae","family":"Hong","sequence":"additional","affiliation":[{"name":"College of Pharmacy Chungbuk National University  Osongsaengmyeong 1\u2010ro, Osong\u2010eup, Heungdeok\u2010gu Cheongju 28160 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sang\u2010Bae","family":"Han","sequence":"additional","affiliation":[{"name":"College of Pharmacy Chungbuk National University  Osongsaengmyeong 1\u2010ro, Osong\u2010eup, Heungdeok\u2010gu Cheongju 28160 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5329-8443","authenticated-orcid":false,"given":"Chun\u2010Woong","family":"Park","sequence":"additional","affiliation":[{"name":"College of Pharmacy Chungbuk National University  Osongsaengmyeong 1\u2010ro, Osong\u2010eup, Heungdeok\u2010gu Cheongju 28160 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seok\u2010Beom","family":"Yong","sequence":"additional","affiliation":[{"name":"Center for Gene &amp; Cell Therapy Korea Research Institute of Bioscience and Biotechnology (KRIBB)  Chungcheongbuk\u2010do 28116 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8182-8963","authenticated-orcid":false,"given":"Hanseul","family":"Park","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Genetics College of Pharmacy Chungbuk National University  Cheongju 28160 Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,12]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1367-5931(00)00082-X"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-020-00654-w"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(00)03196-6"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-12800-x"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ab.2021.114326"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.24976\/Discov.Med.202436185.112"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-015-0173-3"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-021-00272-z"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.4061\/2011\/208634"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20998"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.111.136911"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3871"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2598"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202114797"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.676021"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-023-01481-w"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/adma.202106350"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202301929"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abc9450"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-023-00751-6"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.1c00916"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.4594"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-36519-8"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3697"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2010.09.007"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.14201"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2013.12.009"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.01.001"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41578-021-00358-0"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.3c00371"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202404234"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.nanolett.4c05186"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmaterialslett.3c01642"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.colsurfb.2022.112999"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2010.19"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.245993"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.05.093"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2015.10.049"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2023.106150"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-024-00740-w"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-2010-1221"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25137333"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2023.114990"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41565-019-0591-y"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpharm.2021.120586"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202503725","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.202503725","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202503725","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T12:01:31Z","timestamp":1769688091000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202503725"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,12]]},"references-count":45,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/advs.202503725"],"URL":"https:\/\/doi.org\/10.1002\/advs.202503725","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,12]]},"assertion":[{"value":"2025-02-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e03725"}}