Synergistic Silencing of Skp2 by siRNA Self ‐Assembled Nanoparticles as a Therapeutic Strategy for Advanced Prostate Cancer

Carrier-free delivery of siRNA targeting oncogenicSkp2 is achieved by self-assembly of siSkp2 with quercetin (Que) into nanoparticle. The constructed siSkp2/Que nanoparticles exhibit a synergistic silencing effect by simultaneous degradation of mRNA and protein ofSkp2, leading to apoptosis and proliferation inhibition in advanced prostate cancer cells both in vitro and in vivo. AbstractAdvanced prostate cancer, harboring multiple mutations of tumor suppressor genes, is refractory to conventional therapies. Knockout of theSkp2 gene blocks pRb/p53 doubly deficient prostate cancer in mice, which inspired the authors to develop an approach for delivering siRNA that would efficiently silenceSkp2 (siSkp2) in vivo. Here, a facile strategy is reported to directly assemble siSkp2 with the natural compound quercetin (Que) into supramolecular nanoparticles (NPs). This carrier-free siSkp2 delivery system could effectively protect siSkp2 from degradation in serum and enhance its cellular internalization. Furthermore, the siSkp2/Que NPs exhibit synergistic effects in Skp2 silencing, because they can degrade the mRNA and protein ofSkp2 simultaneously. Indeed, siSkp2/Que NPs remarkably diminish the Skp2 abundance and further inhibit the proliferation and migration of TMU cells (RB1/TP53/KRAS triple mutations) in vitro. The in vivo results further show that i.v. administration of siSkp2/Que NPs efficiently accumulates in tumor sites and strongly inhibits the growth of TMU tumors in nude mice....

Source: Small - February 19, 2022 Category: Nanotechnology Authors: Hong Liang, Fangming Zhang, Yannv Hong, Yue Wu, Huanzhang Xie, Chen Zhang, Zonghua Wang, Zhonglei Lu, Huanghao Yang Tags: Research Article Source Type: research