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However, microglial metabolism is defective overall in AD, thereby undermining microglial phagocytic functions. Herein, we repurpose the existing antineoplastic drug lonidamine (LND) conjugated with hollow mesoporous Prussian blue (HMPB) as a \u201cmicroglial energy modulator\u201d (termed LND@HMPB\u2010T7) for safe and synergistic A\u03b2 clearance. The modified blood\u2013brain barrier penetrating heptapeptide (T7) enables efficient transport of LND@HMPB\u2010T7 to the AD brain. LND in LND@HMPB\u2010T7 could fuel A\u03b2 phagocytosis by stimulating microglial adenosine triphosphate (ATP) production, whereas HMPB with catalase and superoxide dismutase\u2010mimicking activities substantially alleviates the mitochondrial side effects commonly associated with LND and thus further enhances ATP production. The synergism of LND and nanozyme affords a high microglial A\u03b2 clearance efficacy without triggering mitochondrial dysfunction. In vivo experiments ascertain that LND@HMPB\u2010T7 could synergistically promote phagocytic clearance of A\u03b2, relieve neuroinflammation and ameliorate cognitive function in AD mice. These findings indicate that LND@HMPB\u2010T7 holds tremendous clinical potential as a repurposed drug for AD treatment.<\/jats:p>","DOI":"10.1002\/anie.202420547","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T10:59:07Z","timestamp":1734951547000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["A Self\u2010Reinforced \u201cMicroglia Energy Modulator\u201d for Synergistic Amyloid\u2010\u03b2 Clearance in Alzheimer's Disease Model"],"prefix":"10.1002","volume":"64","author":[{"given":"Mengmeng","family":"Ma","sequence":"first","affiliation":[{"name":"School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University  21 Nanyang Link Singapore 637371 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Wenzhou Medical University  Wenzhou, Zhejiang 325035 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiming","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Wenzhou Medical University  Wenzhou, Zhejiang 325035 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbin","family":"Zhong","sequence":"additional","affiliation":[{"name":"School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University  21 Nanyang Link Singapore 637371 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Cheng","sequence":"additional","affiliation":[{"name":"School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University  21 Nanyang Link Singapore 637371 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences Wenzhou Medical University  Wenzhou, Zhejiang 325035 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9231-8360","authenticated-orcid":false,"given":"Yanli","family":"Zhao","sequence":"additional","affiliation":[{"name":"School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University  21 Nanyang Link Singapore 637371 Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,7]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13016"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-022-01565-z"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.25259\/JNRP_356_2023"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2023.102012"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1177\/10600280231218253"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2024.01.047"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02505-2"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.9b03503"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1422998112"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3869"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-43929-1"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202004317"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-020-0397-4"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-020-0072-x"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2209177120"},{"key":"e_1_2_7_16_1","first-page":"1946","volume":"18","author":"Leng L.","year":"2023","journal-title":"Neural. 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