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

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.