Evolution of peptide-mediated siRNA delivery – from early design to next generation platform

Small interfering RNA (siRNA) therapeutics has huge potential for treating many diseases, including those incurable or undruggable by small molecules or antibodies, by harnessing RNA interference (RNAi) to achieve specific silencing of disease-associated genes. To date, all approved siRNA drugs are limited to liver targeting, largely due to delivery challenges. The two siRNA delivery platforms used clinically, namely lipid nanoparticles (LNPs) and N-acetylgalactosamine (GalNAc)-conjugation, are optimized for liver accumulation, restricting broader tissue targeting. Peptides offer a versatile approach to enhance siRNA delivery efficiency by functionalizing nanoparticles as surface ligands to enable specific cell targeting, facilitating cellular uptake and promoting endosomal escape. Alternatively, they can be used as standalone delivery system through complexation or covalent conjugation with siRNA while still fulfilling these roles. Over the years, the development of peptide-based siRNA delivery system has evolved from naturally occurring sequences, rational design, to phage display screening, with emerging machine-learning (ML) approaches expected to accelerate the discovery of novel peptides. This special report highlights the development of peptide-based delivery systems and discusses future directions toward next-generation siRNA delivery platforms to facilitate their successful clinical translation.