ROS-responsive polymeric siRNA nanomedicine stabilized by triple interactions for the robust glioblastoma combinational RNAi therapy
ROS-responsive polymeric siRNA nanomedicine stabilized by triple interactions for the robust glioblastoma combinational RNAi therapy
复制标题
通过三重相互作用稳定 ROS 响应聚合 siRNA 纳米药物，用于强效胶质母细胞瘤组合 RNAi 疗法
DOI：
10.1002/adma.201903277
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发表时间：
2019
影响因子：
29.4
通讯作者：
Shi Bingyang
中科院分区：
文献类型：
--
作者：
Zheng Meng;Liu Yuanyuan;Wang Yibin;Zhang Dongya;Zou Yan;Ruan Weimin;Yin Jinlong;Tao Wei;Park Jong Bae;Shi Bingyang
小干扰RNA （Small interfering RNA, siRNA）在治疗难治性疾病方面具有固有的优势和巨大的潜力。然而，缺乏合适的siRNA传递系统，显示出良好的循环稳定性和有效的现场传递能力，目前阻碍了siRNA的治疗性能。本文构建了一种由三重相互作用（静电、氢键和疏水）稳定的聚合siRNA纳米药物（3I‐NM@siRNA）。与仅依靠静电相互作用维持稳定性的siRNA纳米药物类似物相比，加入额外的氢和疏水相互作用显着提高了生理稳定性。开发的3I‐NM@siRNA纳米药物表明，由肿瘤活性氧（ROS）触发的序列不稳定导致的siRNA释放有效。此外，3I‐NM@siRNA在治疗胶质母细胞瘤（GBM）方面的效用通过血管生成素- 2肽功能化3I‐NM@siRNA纳米药物得到增强。靶向的Ang‐3I‐NM@siRNA具有出色的血脑屏障穿透能力和强大的肿瘤蓄积能力。此外，通过共同靶向polo样激酶1和血管内皮生长因子受体- 2，Ang‐3I‐NM@siRNA显示出有效抑制肿瘤生长并显着提高原位GBM脑肿瘤裸鼠的生存时间。新型siRNA纳米药物具有三重相互作用稳定性和内置的自毁递送能力，为靶向GBM siRNA治疗提供了一个强大而有效的平台，这可能对其他肿瘤或脑部疾病的RNA干扰治疗有实用价值。
Small interfering RNA (siRNA) holds inherent advantages and great potential for treating refractory diseases. However, lack of suitable siRNA delivery systems that demonstrate excellent circulation stability and effective at‐site delivery ability is currently impeding siRNA therapeutic performance. Here, a polymeric siRNA nanomedicine (3I‐NM@siRNA) stabilized by triple interactions (electrostatic, hydrogen bond, and hydrophobic) is constructed. Incorporating extra hydrogen and hydrophobic interactions significantly improves the physiological stability compared to an siRNA nanomedicine analog that solely relies on the electrostatic interaction for stability. The developed 3I‐NM@siRNA nanomedicine demonstrates effective at‐site siRNA release resulting from tumoral reactive oxygen species (ROS)‐triggered sequential destabilization. Furthermore, the utility of 3I‐NM@siRNA for treating glioblastoma (GBM) by functionalizing 3I‐NM@siRNA nanomedicine with angiopep‐2 peptide is enhanced. The targeted Ang‐3I‐NM@siRNA exhibits superb blood–brain barrier penetration and potent tumor accumulation. Moreover, by cotargeting polo‐like kinase 1 and vascular endothelial growth factor receptor‐2, Ang‐3I‐NM@siRNA shows effective suppression of tumor growth and significantly improved survival time of nude mice bearing orthotopic GBM brain tumors. New siRNA nanomedicines featuring triple‐interaction stabilization together with inbuilt self‐destruct delivery ability provide a robust and potent platform for targeted GBM siRNA therapy, which may have utility for RNA interference therapy of other tumors or brain diseases.