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Ribonucleic acid interference therapy is a promising cancer treatment, which uses small interfering RNAs (siRNAs) to target and degrade messenger RNAs. Due to endogenous nuclease activity, siRNA is degraded rapidly, resulting in poor cell uptake and hence specificity. Moreover, it will not readily cross the cell membrane by passive diffusion. In order to take advantage of the therapeutic power of siRNA for the treatment of cancer, specialized delivery vehicles have been designed. In this review, we highlight advances in optimizing nanoparticle functionalization for guided siRNA delivery at the cellular level – that is, promoting cell uptake, escaping the endosome, and releasing siRNA from the delivery vehicle.