Rationally designed tumor-penetrating nanocomplexes.

Small interfering RNA (siRNA) therapeutics have broad potential uses in medicine but require safe and effective delivery vehicles to function. An ideal delivery system should encapsulate and protect the siRNA cargo from serum proteins, exhibit target tissue and cell specificity, penetrate the cell surface, and release its cargo in the desired intracellular compartment. One approach to the design of delivery vehicles that meets all of these requirements utilizes the systematic assembly of multiple components that can address each barrier. This rational approach was adopted by Ren et al., who designed novel myristoylated tandem peptides that consist of a tumor-targeting module and a cell-penetrating module, as described in this issue of ACS Nano. These tandem peptides were formulated with siRNAs into nanocomplexes for cell-specific delivery to a variety of tumor cell lines. The correlation of the structural properties of the nanocomplex to cell-type-specific activity via a computational approach identified the valence of the tumor-targeting ligand and overall nanocomplex charge as important parameters for the activity of the formulations. The in vivo gene silencing potency of these peptide-based nanocomplex formulations was demonstrated by Ren et al. in an ovarian cancer model. Tumor-penetrating nanocomplexes carrying a siRNA sequence against a novel oncogene (ID4) led to a significant reduction in tumor burden and an 80% increase in mouse survival. As such, the combination of a systematic approach with computational modeling can be advantageous for improving the delivery and potency of siRNA therapeutics.