Clinical experiences with systemically administered siRNA-based therapeutics in cancer

Journal name:
Nature Reviews Drug Discovery
Year published:
Published online


Small interfering RNA (siRNA)-based therapies are emerging as a promising new anticancer approach, and a small number of Phase I clinical trials involving patients with solid tumours have now been completed. Encouraging results from these pioneering clinical studies show that these new therapeutics can successfully and safely inhibit targeted gene products in patients with cancer, and have taught us important lessons regarding appropriate dosages and schedules. In this Review, we critically assess these Phase I studies and discuss their implications for future clinical trial design. Key challenges and future directions in the development of siRNA-containing anticancer therapeutics are also considered.

At a glance


  1. Schematic illustrations of the siRNA-based therapeutics used in Phase I trials to treat patients with solid cancers.
    Figure 1: Schematic illustrations of the siRNA-based therapeutics used in Phase I trials to treat patients with solid cancers.

    a | CALAA-01 is a polymer-based nanoparticle containing a targeting ligand on its surface (the human protein transferrin) and a small interfering RNA (siRNA) that targets the M2 subunit of ribonucleotide reductase (RRM2). b | ALN-VSP is a lipid-based nanoparticle that contains two different siRNAs that target vascular endothelial growth factor A (VEGFA) and kinesin spindle protein (KSP). c | Atu27 is a lipid-based nanoparticles that contains an siRNA that targets protein kinase N3 (PKN3). d | TKM-PLK1 is a lipid-based nanoparticle that contains an siRNA that targets polo-like kinase 1 (PLK1). e | PNT2258 is a lipid-based nanoparticle that contains single-stranded DNA (rather than siRNA) that targets BCL2.

  2. Schematic illustration of systemic delivery of siRNA via nanoparticles.
    Figure 2: Schematic illustration of systemic delivery of siRNA via nanoparticles.

    There are many functions that must be performed at the right place and at the right time to produce an antitumour effect with small interfering RNA (siRNA) that is systemically administered to a patient with cancer. First, the nanoparticle formulation is administered intravenously to the patient (steps 1 and 2). The nanoparticles must circulate, reach the tumours and move through the tumour to contact the cancer cells (step 3). The nanoparticles must engage the surface of the cancer cells (step 4) and be internalized (step 5). As the nanoparticles normally enter cells via endocytosis, they must then actively escape the endocytic pathway and release the siRNA into the cytoplasm (step 6). The siRNA then must engage the RNAi pathway (step 7) at some point (most of the time the siRNA engages the RNA-induced silencing complex (RISC) but there are also those that engage Dicer). Loaded RISC then cuts mRNA to yield new RNA fragments (step 8) and the loss of mRNA leads to the loss in protein (step 9). AD-PEG, adamantane polyethylene glycol; CDP, cyclodextrin-based polymer; Tf, transferrin. Figure is adapted from Davis, M. E., Fighting cancer with nanoparticle medicines — the nanoscale matters. MRS Bulletin 37, 828–835, reproduced with permission.

  3. Pharmacokinetic scaling across different species.
    Figure 3: Pharmacokinetic scaling across different species.

    a | CALAA-01 in four species. b | Atu027 in monkeys and humans. AUC, area under the curve; Cmax, maximal serum siRNA concentration; siRNA, small interfering RNA. Figure part a is reprinted with permission from Ref. 28; data for part b are from Ref. 31.


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  1. Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.

    • Jonathan E. Zuckerman
  2. Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.

    • Mark E. Davis

Competing interests statement

M.E.D. has stock in and is a consultant to Cerulean Pharma, Avidity NanoMedicines and Intellia Therapeutics.

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Author details

  • Jonathan E. Zuckerman

    Jonathan E. Zuckerman is a pathology resident at the Department of Pathology and Laboratory Medicine, University of California Los Angeles (UCLA), USA. He received his B.A. in biophysics at the Johns Hopkins University, Baltimore, Maryland, USA, his Ph.D. in biochemistry and molecular biophysics from the California Institute of Technology, Pasadena, California, and his M.D. from the David Geffen School of Medicine at UCLA. His research is focused on drug delivery, especially the development and clinical use of RNAi and polymer–drug conjugate-based nanoparticle therapeutics.

  • Mark E. Davis

    Mark E. Davis is the Warren and Katharine Schlinger Professor of Chemical Engineering at the California Institute of Technology, Pasadena, California, USA, and a member of the Comprehensive Cancer Center at the City of Hope, California, and the Jonsson Comprehensive Cancer Center at University of California Los Angeles. He was the first engineer to win the National Science Foundation's Alan T. Waterman Award. He was elected into the National Academy of Engineering in 1997, the National Academy of Sciences in 2006 and the Institute of Medicine of the National Academies in 2011. In 2014, he received the Prince of Asturias Award for Technical and Scientific Research.

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