Journal
ADVANCED MATERIALS
Volume 33, Issue 45, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adma.202104779
Keywords
cation-free; glioblastoma; micelle; siRNA; spherical nucleic acid
Categories
Funding
- National Key Technologies R&D Program of China [2018YFA0209800] Funding Source: Medline
- National Natural Science Foundation of China [32071388, U190411176, 31800841, 52073079, U1804139] Funding Source: Medline
- NHMRC Investigator Grant Funding Source: Medline
- Key Research Program in Colleges and Universities of Henan Province [19zx006] Funding Source: Medline
- Program of Technology Innovation Team in Colleges and Universities of Henan Province [21IRTSTHN028] Funding Source: Medline
- Henan Province Key Research and Promotion Project [192102310456] Funding Source: Medline
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The novel cation-free siRNA micelles show enhanced blood circulation time, superior cell uptake, potent BBB penetration, and no charge-associated toxicity, resulting in outstanding growth inhibition of orthotopic U87MG xenografts and remarkably improved survival benefits for GBM treatment. Additionally, these siRNA micelles display effective drug loading ability, and when combined with temozolomide, they achieve effective synergistic therapy by targeting key drug-resistant pathways. The siRNA micelle nanoparticle serves as a robust and versatile drug co-delivery platform for effective GBM treatment.
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.
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