Nanomedicine (London, England)Aug 1, 2026

Progression of peptide-based delivery systems for siRNA from early designs to advanced platforms

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 3, 2026

Abstract

Peptide-based delivery systems may enhance siRNA therapeutics beyond liver targeting.

Current siRNA drugs are primarily limited to targeting the liver due to delivery challenges.
Lipid nanoparticles and GalNAc-conjugation are the two delivery platforms used clinically, optimized for liver accumulation.
Peptides can improve siRNA delivery by serving as ligands on nanoparticles or as standalone delivery systems.
The evolution of peptide-based delivery systems includes naturally occurring sequences and machine-learning approaches for peptide discovery.
Future directions focus on developing next-generation siRNA delivery platforms for broader clinical applications.

Simplified

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.

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Progression of peptide-based delivery systems for siRNA from early designs to advanced platforms

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