Polyphenol Mediated Assembly: Tailored Nano‐Dredger Unblocks Axonal Autophagosomes Retrograde Transport Traffic Jam for Accelerated Alzheimer's Waste Clearance

Abstract Clear‐cut evidence has linked defective autophagy to Alzheimer's disease (AD). 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‐mitigating microtubule disruption, ATP depletion, oxidative stress, and autophagy initiation impediments in AD. Leveraging the recent discovery of multi‐interactions between polyphenol LA and siRNA, ε‐Poly‐L‐lysine, and anionic lipid nanovacuoles, LA and siROCK2 are successfully co‐loaded into a fresh nano‐drug delivery system, LIP@PL‐LA/siRC, via a ratio‐flexible and straightforward fabrication process. Further modification with the TPL peptide onto LIP@PL‐LA/siRC creates a brain‐neuron targeted, biocompatible, and pluripotent nanomedicine, named “Nano‐dredger” (T‐LIP@PL‐LA/siRC). Nano‐dredger 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×Tg‐AD transgenic mice. This study provides a fresh and flexible polyphenol/siRNA co‐delivery paradigm and furnishes conceptual proof that dredging axonal autophagy represents a promising AD therapeutic avenue.