Enhanced shRNA Delivery and ABCG2 Silencing by Charge-Reversible Layered Nanocarriers
Enhanced shRNA Delivery and ABCG2 Silencing by Charge-Reversible Layered Nanocarriers
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通过电荷可逆层状纳米载体增强 shRNA 递送和 ABCG2 沉默
DOI：
10.1002/smll.201401397
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发表时间：
2015-02-25
期刊：
影响因子：
13.3
通讯作者：
Li, Yanfeng
中科院分区：
文献类型：
--
作者：
Chen, Zhenzhen;Zhang, Lifen;Li, Yanfeng
聚阳离子载体已被用于携带短发夹状RNA(ShRNAs)到肿瘤治疗中的下调基因，但其在溶酶体逃逸和shRNA释放方面的效率低下导致其基因转录效率低下。本论文构建了一种三层聚乙烯亚胺(PEI)包覆金纳米络合物：Au-PEI/CS-ACO/PEI/shRNA纳米粒子，并与pH响应型电荷可逆壳聚糖-乌头酸酐(CS-ACO)相互作用。带负电荷的CS-ACO在溶酶体中水解成带正电荷的CS，导致纳米复合材料解体。释放的Au-PEI纳米颗粒有效地破坏溶酶体，从而将PEI/shRNA多聚体释放到细胞质中，在那里它们迅速解离，因为PEI链较短(1.2 kDa)。结果，该纳米复合体显示出比25 kDa PEI更高的shRNA传递效率，并有效地将shABCG2传递给肿瘤并显著沉默ABCG2的表达，从而以最小的毒性使HepG2细胞对药物敏感。
Polycationic vectors have been used to deliver short hairpin RNAs (shRNAs) to knock-down genes for cancer therapies, but their inefficiency in lysosomal escape and shRNA release causes their low gene transcription efficiency. Herein, a three-layered polyethyleneimine (PEI)-coated gold nanocomplex interlaid with a pH-responsive charge-reversible chitosan-aconitic anhydride (CS-Aco) is constructed: a Au-PEI/ CS-Aco/PEI/shRNA nanoparticle. The negatively charged CS-Aco hydrolyzes into positively charged CS in lysosomes, causing the nanocomposite to disassemble. The released Au-PEI nanoparticles efficiently rupture the lysosomes and thus release the PEI/shRNA polyplexes into cytoplasm, where they quickly disassociate because the PEI chains are short (1.2 kDa). As a consequence, the nanocomplexes display higher shRNA delivery efficiency than the 25 kDa PEI, and efficiently deliver shABCG2 to tumors and markedly silence ABCG2 expression, which sensitizes HepG2 cells to the drugs with minimal toxicity.