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Synthesis, Functionalization, and Characterization of Fusogenic Porous Silicon Nanoparticles for Oligonucleotide Delivery

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Multimeric Conjugates Using Engineered Peptide Scaffolds for Efficient siRNA Delivery.

Quentin Vicentini^1,2, Dennis Hekman³, Deepak Bhatt³

¹Cell, Genes and RNA Therapy, Discovery Sciences, Biopharmaceuticals R&D-AstraZeneca Gothenburg, 43183 Mölndal, Sweden.

Bioconjugate Chemistry

|May 30, 2025

Summary

This summary is machine-generated.

Researchers developed peptide scaffolds to link multiple small interfering RNAs (siRNAs) for enhanced liver delivery. This multimeric approach shows potent gene silencing and improved biodistribution, advancing oligonucleotide therapeutics.

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Area of Science:

Biotechnology
Drug Delivery
Molecular Biology

Background:

Oligonucleotide therapeutics (ONT) traditionally use single targeting moieties for organ delivery.
Multimerization of ONTs offers enhanced tissue retention, extended silencing, and multi-gene targeting capabilities.

Purpose of the Study:

To engineer a versatile peptide branching unit for multimerizing small interfering RNAs (siRNAs).
To evaluate the efficacy of peptide-based multimeric siRNA conjugates for liver delivery and gene silencing.

Main Methods:

Engineered peptide branching units to link up to four siRNAs.
Conjugated GalNAc targeting moieties for hepatocyte delivery.
Explored linear and cyclized peptide architectures with endosomal escape domains and dual-target silencing.
Assessed constructs via subcutaneous and intravenous administration in mice.

Main Results:

Intravenous administration of multimeric siRNA GalNAc conjugates demonstrated potent liver gene silencing.
Significantly altered liver-to-kidney biodistribution was observed.
Peptide branching units proved effective in multimerizing siRNA for enhanced delivery.

Conclusions:

Peptide branching units represent a promising strategy for oligonucleotide therapeutic multimerization.
This approach advances challenges in drug delivery for enhanced therapeutic outcomes.