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Although the pathophysiology of AD remains debatable, its progression is strongly correlated with the accumulation of tau aggregates. Therefore, tau clearance from brain lesions can be a promising strategy for AD therapy. To achieve this, the present study combined proteolysis\u2010targeting chimera (PROTAC), a novel protein\u2010degradation technique that mediates degradation of target proteins via the ubiquitin\u2010proteasome system, and a neurotransmitter\u2010derived lipidoid (NT\u2010lipidoid) nanoparticle delivery system with high blood\u2010brain barrier\u2010penetration activity, to generate a novel nanomedicine named NPD. Peptide 1, a cationic tau\u2010targeting PROTAC is loaded onto the positively charged nanoparticles using DNA\u2010intercalation technology. The resulting nanomedicine displayed good encapsulation efficiency, serum stability, drug release profile, and blood\u2010brain barrier\u2010penetration capability. Furthermore, NPD potently induced tau clearance in both cultured neuronal cells and the brains of AD mice. Moreover, intravenous injection of NPD led to a significant improvement in the cognitive function of the AD mice, without any remarkable abnormalities, thereby supporting its clinical development. Collectively, the novel nanomedicine developed in this study may serve as an innovative strategy for AD therapy, since it effectively and specifically induces tau protein clearance in brain lesions, which in turn enhances cognition.<\/jats:p>","DOI":"10.1002\/adhm.202400149","type":"journal-article","created":{"date-parts":[[2024,7,15]],"date-time":"2024-07-15T05:57:49Z","timestamp":1721023069000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Systemic Administration of Neurotransmitter\u2010Derived Lipidoids\u2010PROTACs\u2010DNA Nanocomplex Promotes Tau Clearance and Cognitive Recovery for Alzheimer's Disease Therapy"],"prefix":"10.1002","volume":"13","author":[{"given":"Baofeng","family":"Gong","sequence":"first","affiliation":[{"name":"Department of Neurology Second Affiliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University Shanghai 200003 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weicong","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Pharmacy University College London London WC1N 1AX UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Cong","sequence":"additional","affiliation":[{"name":"School of Medicine Shanghai University Shanghai 200444 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuankai","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Neurology Second Affiliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University Shanghai 200003 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbo","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Neurology Second Affiliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University Shanghai 200003 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Neurology Second Affiliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University Shanghai 200003 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honglei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of General Surgery First Affiliated Hospital of Nanjing Medical University Nanjing 210029 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honggang","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Medicine Shanghai University Shanghai 200444 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Neurology Second Affiliated Hospital (Shanghai Changzheng Hospital) of Naval Medical University Shanghai 200003 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Luo","sequence":"additional","affiliation":[{"name":"New Drug Discovery and Development Biotheus Inc. 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