内体
内吞作用
细胞生物学
转染
胞浆
小干扰RNA
溶酶体
细胞内
细胞毒性
基因沉默
磷脂病
化学
胞饮病
纳米凝胶
生物
细胞
药物输送
生物化学
体外
膜
基因
有机化学
酶
磷脂
作者
Freya Joris,Lynn De Backer,Thijs Van de Vyver,Chiara Bastiancich,Stefaan C. De Smedt,Koen Raemdonck
标识
DOI:10.1016/j.jconrel.2017.11.019
摘要
Cytosolic delivery remains a major bottleneck for siRNA therapeutics. To facilitate delivery, siRNAs are often enclosed in nanoparticles (NPs). However, upon endocytosis such NPs are mainly trafficked towards lysosomes. To avoid degradation, cytosolic release of siRNA should occur prior to fusion of endosomes with lysosomes, but current endosomal escape strategies remain inefficient. In contrast to this paradigm, we aim to exploit lysosomal accumulation by treating NP-transfected cells with low molecular weight drugs that release the siRNA from the lysosomes into the cytosol. We show that FDA-approved cationic amphiphilic drugs (CADs) significantly improved gene silencing by siRNA-loaded nanogels in cancer cells through simple sequential incubation. CADs induced lysosomal phospholipidosis, leading to transient lysosomal membrane permeabilization and improved siRNA release without cytotoxicity. Of note, the lysosomes could be applied as an intracellular depot for triggered siRNA release by multiple CAD treatments.
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