Peptide carriers to the rescue: overcoming the barriers to siRNA delivery for cancer treatment

Abstract

Cancer is a significant health concern worldwide and its clinical treatment presents many challenges. Consequently, much research effort has focused on the development of new anticancer drugs to combat this disease. One area of exploration, in particular, has been in the therapeutic application of RNA interference (RNAi). Although RNAi appears to be an attractive therapeutic tool for the treatment of cancer, one of the primary obstacles towards its pervasive use in the clinic has been cell/tissue type-specific cytosolic delivery of therapeutic small interfering RNA (siRNA) molecules. Consequently, varied drug delivery platforms have been developed and widely explored for siRNA delivery. Among these candidate drug delivery systems, peptides have shown great promise as siRNA carriers due to their varied physiochemical properties and functions, simple formulations, and flexibility in design. In this review, we will focus on distinguishing between the different classes of peptide carriers based on their functions, as well as summarize and discuss the various design strategies and advancements that have been made in circumventing the barriers to siRNA delivery for cancer treatment. Resolution of these challenges by peptide carriers will accelerate the translation of RNAi-based therapies to the clinic.

Fig 1.

Schematic representation of peptide-mediated siRNA delivery strategies into cells. (A) Cell-penetrating peptides (CPPs), including cationic, amphipathic, and targeting/homing peptides. (B) Endosome-disrupting peptides, including fusogenic, pH-sensitive amphipathic, and proton buffering peptides. (C) Multifunctional peptide complexes. (D) Alternative peptide/protein strategies, including targeting/homing peptide-siRNA bioconjugates and recombinant RNA binding fusion proteins. dsRBD, double-stranded RNA binding domain; RISC, RNA-induced silencing complex.