Cation-free siRNA micelles as effective drug delivery platform and potent RNAi nanomedicines for glioblastoma therapy

Tong Jiang, Yongnan Qiao, Weimin Ruan, Dongya Zhang, Qingshan Yang, Guoying Wang, Qunzhi Chen, Fengping Zhu, Jinlong Yin, Yan Zou, Rongjun Qian, Meng Zheng, Bingyang Shi

Research output: Contribution to journalArticlepeer-review

Abstract

Nanoparticle-based small interfering RNA (siRNA) therapy shows great promise for glioblastoma (GBM). However, charge associated toxicity and limited blood–brain-barrier (BBB) penetration remain significant challenges for siRNA delivery for GBM therapy. Herein, novel cation-free siRNA micelles, prepared by the self-assembly of siRNA-disulfide-poly(N-isopropylacrylamide) (siRNA-SS-PNIPAM) diblock copolymers, are prepared. The siRNA micelles not only display enhanced blood circulation time, superior cell take-up, and effective at-site siRNA release, but also achieve potent BBB penetration. Moreover, due to being non-cationic, these siRNA micelles exert no charge-associated toxicity. Notably, these desirable properties of this novel RNA interfering (RNAi) nanomedicine result in outstanding growth inhibition of orthotopic U87MG xenografts without causing adverse effects, achieving remarkably improved survival benefits. Moreover, as a novel type of polymeric micelle, the siRNA micelle displays effective drug loading ability. When utilizing temozolomide (TMZ) as a model loading drug, the siRNA micelle realizes effective synergistic therapy effect via targeting the key gene (signal transducers and activators of transcription 3, STAT3) in TMZ drug resistant pathways. The authors’ results show that this siRNA micelle nanoparticle can serve as a robust and versatile drug codelivery platform, and RNAi nanomedicine and for effective GBM treatment.
Original languageEnglish
Article number2104779
Number of pages10
JournalAdvanced Materials
DOIs
Publication statusE-pub ahead of print - 18 Sep 2021

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