Many animal studies have shown the therapeutic potential of using small interfering RNAs (siRNAs) to reduce expression of target genes. Although clinical trials with siRNA are underway for a range of diseases1, it has not yet been demonstrated that delivery of siRNA can trigger RNA interference (RNAi) in humans. For instance, in a clinical trial of intravitreal siRNA for the treatment of blinding choroidal neovascularization, the contribution of non-RNAi mechanisms to the decrease in vascularization could not be eliminated2.

Now, Davis et al.3 report in Nature that siRNA engages the human RNAi machinery to reduce expression of the M2 subunit of ribonucleotide reductase at both the mRNA and protein levels. The study, which is part of a phase 1 clinical trial of systemic siRNA treatment for patients with solid cancers, involved examining biopsies from just three melanoma patients who had received intravenous infusions of siRNA delivered using synthetic nanoparticles.

The nanoparticles (∼70-nm diameter) were stabilized by adamantane (AD)-terminated polyethylene glycol (PEG) complexed with a cyclodextrin-based polymer (CDP). Inclusion of the human transferrin (TF) protein on the exposed ends of some of the PEG molecules targeted the nanoparticles to cancer cells expressing the TF receptor.

The authors use 5-nm gold particles to detect the nanoparticles in tumor cells, demonstrating what they believe is the first demonstration of dose-dependent accumulation of systemically delivered targeted nanoparticles in human tumors.

Characterization of the mRNA cleavage products using a modified 5′-RNA-ligand–mediated 'Rapid Amplification of cDNA Ends' method provided mechanistic evidence that the specific siRNAs engaged the RNA interference apparatus. Details of the efficacy of the approach in causing tumor regression have yet to be reported.