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CANCER NANOMEDICINE

Efficient siRNA delivery with non-cationic carriers

Nature Biomedical Engineering volume 2, pages 275–276 (2018)Cite this article

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Self-assembled weakly negative nanoparticles bearing an octet of short interfering RNAs, targeting ligands and endosomolytic peptides lead to efficient gene silencing in a mouse model of prostate cancer.

When taking advantage of RNA interference (RNAi) — a pathway for the post-transcriptional silencing of genes via short interfering RNAs (siRNAs) — as a therapeutic approach to fighting cancer1, nanoparticles can be used to endow siRNAs with prolonged blood circulation, with resistance against degradation by serum nucleases, and with the ability to target tumours, actively by ligand–receptor binding or passively via the enhanced permeability and retention (EPR) effect2. The inhibition of cancer genes in humans by RNAi, with the first phase-I clinical trial of systemically administered siRNA-containing targeted cationic polymeric nanoparticles to cancer patients reported in 2010 (ref. 3) and with several other classes of siRNA-carrying nanoparticles undergoing phase-I and phase-II clinical trials2, has revealed that significant translational obstacles remain. In particular, there is low accumulation of nanoparticles in tumours; typically, less than 1% of the systemically injected dose reaches the tumour, partially due to nanoparticle sequestration by the mononuclear phagocyte system and to biophysical constraints imposed by the tumour, such as elevated interstitial fluid pressure and the presence of the extracellular matrix4. Also, most siRNA-containing nanoparticles can be toxic to animals and humans5, because the nanoparticles are prepared by electrostatically complexing siRNAs with excess cationic polymers or lipids. The excess cationic components also make the nanoparticles susceptible to disassembly at the glomerular basement membrane, resulting in renal clearance of the siRNAs6. Following the uptake of siRNA-carrying nanoparticles by cancer cells, the siRNAs should escape from the endosomes into the cytoplasm to achieve gene silencing. Despite the recently improved understanding of endosomal-escape mechanisms7, only 1–2% of the siRNAs internalized by the cells can reach the cytoplasm8. Reporting in Nature Biomedical Engineering, Xiaohu Gao and colleagues now show that weakly negative ribonucleoprotein–siRNA nanoparticles can help address these delivery challenges. In mouse models of prostate cancer, the authors demonstrate that the nanoparticles effectively silence a cancer gene, delay tumour growth and exhibit low immunogenicity9.

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Fig. 1: Non-cationic nanostructures for in vivo gene silencing via RNAi.

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Authors and Affiliations

  1. Department of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, Hong Kong

    Chun Kit K. Choi, Lei Zhang & Chung Hang Jonathan Choi

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  1. Chun Kit K. Choi
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  2. Lei Zhang
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  3. Chung Hang Jonathan Choi
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Correspondence to Chung Hang Jonathan Choi.

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Choi, C.K.K., Zhang, L. & Choi, C.H.J. Efficient siRNA delivery with non-cationic carriers. Nat Biomed Eng 2, 275–276 (2018). https://doi.org/10.1038/s41551-018-0240-z

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