Small interfering RNA (siRNA) that inhibit the formation of α-synuclein (α-syn) aggregates is considered very promising therapeutic agents for the treatment of Parkinson's disease (PD). However, the low stability and the difficulty in crossing the blood-brain barrier (BBB) of free siRNA has severely limited their therapeutic effects. Here, we developed an H2S donor nanomotor that can encapsulate siRNA, which can both protect the activity of siRNA and help siRNA to be effectively targeted to the mitochondria of damaged neuronal cells, in order to promote the effective therapeutic effect of siRNA for PD. Specifically, the cysteine monomer-modified polyethylene glycol (PEG-Cys) and the amphiphilic ionic monomer 2-methacryloyloxyethylphosphorylcholine (MPC) that can effectively penetrate the BBB, were selected to form a polymer protective layer on the surface of siRNA in a free-radical polymerization reaction, to construct the H2S donor nanomotor encapsulating siRNA (PCM@siRNA). Among them, MPC can help PCM@siRNA to break through the BBB by interacting with nicotinic acetylcholine receptor or choline transporter on the surface of cerebrovascular endothelial cells, while PEG-Cys can undergo chemotactic effect by specifically recognizing 3-thiopyruvate thioltransferase and thus achieve effective targeting of damaged mitochondria in neuronal cells. PCM@siRNA that reached neuronal cells can not only be utilized to play the role of silencing the α-syn gene to inhibit the formation of α-syn aggregates by siRNA, but also to degrade the formed α-syn aggregates by using the H2S produced by its chemotaxis process to achieve an effective treatment for PD. This therapeutic modality, which can simultaneously inhibit the formation of α-syn aggregates and promote their degradation, has the therapeutic potential to reverse the pathological state of α-syn, which is important for the treatment of PD.

中文翻译：

---

通过释放硫化氢的纳米马达递送小干扰 RNA 治疗帕金森病


抑制 α-突触核蛋白 （α-syn） 聚集体形成的小干扰 RNA （siRNA） 被认为是治疗帕金森病 （PD） 的非常有前途的治疗剂。然而，游离 siRNA 的低稳定性和难以穿过血脑屏障 （BBB） 严重限制了它们的治疗效果。在这里，我们开发了一种可以封装 siRNA 的 H2S 供体纳米马达，它既可以保护 siRNA 的活性，又可以帮助 siRNA 有效地靶向受损神经元细胞的线粒体，以促进 siRNA 对 PD 的有效治疗效果。具体来说，半胱氨酸单体修饰的聚乙二醇 （PEG-Cys） 和两亲性离子单体 2-甲基丙烯酰氧乙基磷酸胆碱 （MPC） 可以有效穿透 BBB， 在自由基聚合反应中，选择在 siRNA 表面形成聚合物保护层，以构建 H2S 供体纳米马达封装 siRNA （PCM@siRNA）。其中，MPC 可通过与脑血管内皮细胞表面的烟碱乙酰胆碱受体或胆碱转运蛋白相互作用，帮助 PCM@siRNA 突破 BBB，而 PEG-Cys 可通过特异性识别 3-硫代丙酮酸硫醇转移酶而发挥趋化作用，从而有效靶向神经元细胞中受损的线粒体。到达神经元细胞的PCM@siRNA不仅可以用于沉默 α-syn 基因以抑制 siRNA 形成 α-syn 聚集体，还可以通过利用其趋化过程产生的 H2S 降解形成的 α-syn 聚集体，从而实现对 PD 的有效治疗。 这种治疗方式可以同时抑制 α-syn 聚集体的形成并促进其降解，具有逆转 α-syn 病理状态的治疗潜力，这对 PD 的治疗很重要。