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Clinical experiences with systemically administered siRNA-based therapeutics in cancer

Key Points

  • Several Phase I trials evaluating the use of siRNA for the treatment of solid cancers have now been completed.

  • All trials to date have used nanoparticle-based delivery systems to transport therapeutic siRNA to tumours following systemic administration.

  • Despite concerns about potential overwhelming immunostimulation following systemic siRNA administration in humans, the data reported to date for clinically evaluated siRNA therapeutics (both naked and chemically modified siRNA) have shown these therapeutics to be well tolerated, with only modest and treatable immunostimulatory reactions.

  • Successful delivery of functional siRNA to human tumours has been demonstrated in multiple trials, providing proof-of-principle for RNAi- based therapeutics in humans.

  • Results from these trials show that safe target gene inhibition can be achieved in patients, when systemically treated twice per week with either lipid- or polymer-based nanoparticle formulations containing siRNAs at doses in the 0.5–1.0 mg siRNA per kg range.


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.

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Figure 1: Schematic illustrations of the siRNA-based therapeutics used in Phase I trials to treat patients with solid cancers.
Figure 2: Schematic illustration of systemic delivery of siRNA via nanoparticles.
Figure 3: Pharmacokinetic scaling across different species.


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Corresponding author

Correspondence to Mark E. Davis.

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Competing interests

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

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PowerPoint slides


RNA interference

(RNAi). An intrinsic pathway in eukaryotic cells by which short pieces of RNA are able to induce the degradation of mRNA transcripts containing a complementary sequence.

Small interfering RNA

(siRNA). Synthetic double-stranded RNA molecules approximately 21–23 nucleotides long that are capable of engaging the intrinsic RNAi pathway when delivered to the cellular cytoplasm.

Systemic administration

A route of administration of a drug into the circulatory system so that the entire body is affected. In the nanoparticle therapeutic field, this usually refers to intravenous administration.

RNA-induced silencing complex

(RISC). The protein complex responsible for the identification and destruction of the target mRNA when engaged by siRNA.


Generally refers to particles between 1 and 100 nm in size.


A broad category of drug delivery vehicles based on a backbone of lipid bilayers.


A large group of proteins, peptides or glycoproteins that are secreted by specific cells of the immune system. Cytokines are a category of signalling molecules that mediate and regulate immunity, inflammation and haematopoiesis.


An innate part of the mammalian immune system that complements the ability of antibodies and phagocytic cells to clear pathogens from an organism.

eastern Cooperative Oncology Group performance status

A quantification of the general well-being, daily activity and physical ability of a patient with cancer. In the setting of a clinical trial, set performance status cut-off levels are one criterion used to determine eligibility for trial enrolment and treatment.


The study of the biochemical and physiological effects of a drug on the body, including mechanistic action, duration of action, therapeutic effects and toxicities.


The movement of a drug into, through and out of the body; that is, its absorption, bioavailability, distribution, metabolism and excretion.

Enhanced permeability and retention effect

A phenomenon whereby macromolecules and nanoparticles passively accumulate within tumour tissue from the bloodstream. The mechanism behind this phenomenon is poorly understood and is thought to be partially due to the increased permeability of tumour vasculature and poor tumour lymphatic drainage.

CRISPR system

An RNA-guided gene-editing platform that utilizes the bacterial protein Cas9 and a synthetic guide RNA to introduce a double-stranded DNA break at a specific location within the genome.

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Zuckerman, J., Davis, M. Clinical experiences with systemically administered siRNA-based therapeutics in cancer. Nat Rev Drug Discov 14, 843–856 (2015).

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