期刊
JOURNAL OF CONTROLLED RELEASE
卷 269, 期 -, 页码 266-276出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2017.11.019
关键词
Drug repurposing; siRNA delivery; Nanogels; Phospholipidosis; Lysosomal membrane permeabilization; Cationic amphiphilic drugs
资金
- Ghent University [BOF12/GOA/014]
- FWO [1517516N]
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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