DS0305 -

Non-Covalent Tagging of siRNA Oligonucleotides with Short Block Copolymer Sequences for Improved Targeted Delivery – TANGO

Submission summary

RNA interference (RNAi) induced by small interfering RNA (siRNA) holds the promise to treat several diseases which cannot be treated today with conventional methods. However, a major issue for siRNA-based therapeutics concerns the effective delivery of siRNA oligonucleotides to their sites of action in the cytoplasm. As a consequence, pharmaceutical companies and academic institutions are actively seeking to develop safe and effective delivery methods. Among them, chemical conjugates of siRNA with various ligands and nanocarriers assembled from polymers or lipids have been widely studied and used as delivery systems. Molecular-sized chemical conjugates have the advantage of being well-defined molecular entities that are able to access virtually all tissues, just as conventional drugs. However, each conjugate requires a separate synthesis. In addition, the covalent attachment of a ligand generally reduces the gene silencing activity of the siRNA significantly. Self-assembled nanocarriers can combine a large payload of siRNA with a high affinity to the target cells through the multivalent presentation of targeting ligands. However, despite advances in using PEG or other strategies to shield the nanoparticles, a large fraction of injected nanoparticles accumulates in the liver. Therefore, there is still much room for innovation and improvement in the design of siRNA delivery materials. In the TANGO project we aim at proposing an approach which combines the precision and molecular size of conjugates with the ease and versatility of the electrostatic complexation. Namely, the idea is to design non-covalent conjugates through electrostatic interaction between chitosan-block-PEG copolymer and siRNA. The novelty consists in using ultra small and well-defined blocks of positively charged chitosan in order to form true monomolecular complexes featuring a single siRNA molecule electrostatically complexed with a defined number of chitosan-PEG copolymers. The proposed structure is thus fundamentally different from polyplexes or even polyion complex micelles where several siRNA molecules are complexed within a particle. The degree of PEGylation, the PEG block length and the PEG branching can be adjusted trough the initial composition of the block copolymer which then makes the overall approach quite flexible. The conjugates can be decorated with targeting ligands in a multivalent fashion by modifying the PEG-end chains with suitable ligands. In the proposal, the chitosan-PEG copolymer contains a hydrazone bond which should favour the PEG unshielding in acidic endosomal compartments and therefore improve the release of siRNA. The project is built around three mains tasks involving competencies in chemistry to prepare small chitosan blocks and synthesize a library of copolymers, competencies in physical chemistry to study the formation and characterization of the conjugates in a large range of conditions and competencies in pharmacy and biology to evaluate the potential of the conjugates in vitro and in vivo with a siRNA able to block proinflammatory cytokines involved in the pathogenesis of rheumatoid arthritis. If the non-covalent PEGylation method could bring the same benefits as the covalent PEGylation through a simpler and more flexible approach, this may contribute to fundamental research in fields like RNA interference as well as to the translation to therapeutics.

Project coordination

Christophe Schatz (Laboratoire de Chimie des Polymères Organiques)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


IMP@LYON UMR 5223 Laboratoire d'Ingénierie des Matériaux Polymères
IGPS UMR 8612 Institut Galien Paris-Sud
LCPO UMR 5629 Laboratoire de Chimie des Polymères Organiques

Help of the ANR 497,880 euros
Beginning and duration of the scientific project: January 2017 - 42 Months

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