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Recent studies underscore a unique hurdle in AD neuronal autophagy: impaired retrograde axonal transport of autophagosomes, potent enough to induce autophagic stress and neurodegeneration. Nonetheless, pertinent therapy is unavailable. Here, a novel combinational therapy composed of siROCK2 and lithospermic acid B (LA) is introduced, tailored to dredge blocked axonal autophagy by multi\u2010mitigating microtubule disruption, ATP depletion, oxidative stress, and autophagy initiation impediments in AD. Leveraging the recent discovery of multi\u2010interactions between polyphenol LA and siRNA, \u03b5\u2010Poly\u2010L\u2010lysine, and anionic lipid nanovacuoles, LA and siROCK2 are successfully co\u2010loaded into a fresh nano\u2010drug delivery system, LIP@PL\u2010LA\/siRC, via a ratio\u2010flexible and straightforward fabrication process. Further modification with the TPL peptide onto LIP@PL\u2010LA\/siRC creates a brain\u2010neuron targeted, biocompatible, and pluripotent nanomedicine, named \u201cNano\u2010dredger\u201d (T\u2010LIP@PL\u2010LA\/siRC). Nano\u2010dredger efficiently accelerates axonal retrograde transport and lysosomal degradation of autophagosomes, thereby facilitating the clearance of neurotoxic proteins, improving neuronal complexity, and alleviating memory defects in 3\u00d7Tg\u2010AD transgenic mice. This study provides a fresh and flexible polyphenol\/siRNA co\u2010delivery paradigm and furnishes conceptual proof that dredging axonal autophagy represents a promising AD therapeutic avenue.<\/jats:p>","DOI":"10.1002\/adma.202413614","type":"journal-article","created":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T03:43:52Z","timestamp":1734407032000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Polyphenol Mediated Assembly: Tailored Nano\u2010Dredger Unblocks Axonal Autophagosomes Retrograde Transport Traffic Jam for Accelerated Alzheimer's Waste Clearance"],"prefix":"10.1002","volume":"37","author":[{"given":"Ran","family":"Meng","sequence":"first","affiliation":[{"name":"Key Laboratory of Smart Drug Delivery Ministry of Education, National Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers School of Pharmacy Fudan University  Shanghai 201203 P. R. 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