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.

中文翻译：

---

多酚介导的组装：量身定制的纳米疏浚剂疏通轴突自噬体逆行运输拥堵，加速阿尔茨海默病废物清除


明确的证据表明，有缺陷的自噬与阿尔茨海默病 （AD） 有关。最近的研究强调了 AD 神经元自噬的一个独特障碍：自噬体的逆行轴突运输受损，足以诱导自噬应激和神经退化。尽管如此，目前尚无相关治疗。在这里，介绍了一种由 siROCK2 和岩石精酸 B （LA） 组成的新型联合疗法，旨在通过多缓解 AD 中的微管破坏、ATP 耗竭、氧化应激和自噬起始障碍来疏通受阻的轴突自噬。利用最近发现的多酚 LA 和 siRNA、ε-聚-L-赖氨酸和阴离子脂质纳米液泡之间的多重相互作用， LA 和 siROCK2 通过比率灵活且简单的制造工艺成功共加载到新的纳米药物递送系统 LIP@PL-LA/siRC 中。用 TPL 肽对 LIP@PL-LA/siRC 进行进一步修饰，产生一种脑神经元靶向、生物相容性和多能纳米药物，称为“纳米挖泥船”（T-LIP@PL-LA/siRC）。纳米挖泥机可有效加速自噬体的轴突逆行转运和溶酶体降解，从而促进神经毒性蛋白的清除，提高神经元复杂性，并减轻 3×Tg-AD 转基因小鼠的记忆缺陷。这项研究提供了一种新鲜而灵活的多酚/siRNA 共递送范式，并提供了概念证据，证明疏通轴突自噬代表了一条有前途的 AD 治疗途径。