Alpha-synuclein (α-syn) deposition in Lewy bodies (LB) is one of the main neuropathological hallmarks of Parkinson’s disease (PD). LB accumulation is considered a causative factor of PD, which suggests that strategies aimed at reducing α-syn levels could be relevant for its treatment. In the present study, we developed novel nanocarriers suitable for systemic delivery of small interfering ribonucleic acid (siRNA) that were specifically designed to reduce neuronal α-syn by RNA interference. Anionic liposomes loaded with an siRNA–protamine complex for α-syn gene silencing and decorated with a rabies virus glycoprotein (RVG)-derived peptide as a targeting agent were prepared. The nanoparticles were characterized for their ability to load, protect, and deliver the functional siRNA to mouse primary hippocampal and cortical neurons as well as their efficiency to induce gene silencing in these cells. Moreover, the nanocarriers were evaluated for their stability in serum. The RVG-decorated liposomes displayed suitable characteristics for future in vivo applications and successfully induced α-syn gene silencing in primary neurons without altering cell viability. Collectively, our results indicate that RVG-decorated liposomes may be an ideal tool for further studies aimed at achieving efficient in vivo α-syn gene silencing in mouse models of PD.

中文翻译：

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用于将小干扰核糖核酸（siRNA）递送至原代神经元细胞的阴离子脂质体：α-突触核蛋白敲低功效的评估

路易体（LB）中的α-突触核蛋白（α - syn）沉积是帕金森氏病（PD）的主要神经病理学标志之一。LB的积累被认为是PD的病因，这表明旨在降低α- syn水平的策略可能与其治疗有关。在本研究中，我们开发了适用于全身性传递小干扰核糖核酸（siRNA）的新型纳米载体，这些载体是专门设计用于通过RNA干扰减少神经元α- syn的。载有siRNA-鱼精蛋白复合物的α阴离子脂质体-syn基因沉默，并用狂犬病病毒糖蛋白（RVG）衍生的肽作为靶向剂进行修饰。纳米颗粒的特征在于其将功能性siRNA装载，保护和递送至小鼠原代海马和皮层神经元的能力，以及在这些细胞中诱导基因沉默的效率。此外，评估了纳米载体在血清中的稳定性。RVG修饰的脂质体在未来的体内应用中显示出合适的特性，并在不改变细胞活力的情况下成功地诱导了原代神经元中的α- syn基因沉默。总的来说，我们的结果表明，RVG装饰的脂质体可能是进一步研究的理想工具，旨在实现有效的体内αPD小鼠模型中的-syn基因沉默。