[Baseclick Newsletter] How to deliver your target Oligonucleotide into cells?_BaseClick - 코아사이언스

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How to deliver your target Oligonucleotide into cells?

Targeted delivery of Oligonucleotides (Oligos) to cells is a critical aspect of therapeutic approaches in gene therapy, RNA interference (RNAi), antisense RNA therapy or CRISPR-Cas9. Efficient delivery systems are required to ensure that the Oligos reach their target tissue and cells, avoid degradation by nucleases and penetrate the cell to access intracellular targets.
In this newsletter we have compared two different conventional methods, Lipid-based Nanoparticles and Sugar based delivery systems, as tools for the transport of Oligos into cells.

 

Mechanism of Sugar-Based Targeting and LNPs

Sugar-targeting is based on the interaction between glycans and lectin type receptors on the surface of cells. Many cells express surface receptors that bind specific carbohydrates, e.g.
Asialoglycoprotein receptor (ASGPR): Expressed on liver cells have a strong affinity for N-acetylgalactosamine (GalNAc). The mannose receptor CD206 is found on macrophages and dendritic cells that can be addressed with mannose-based glycans.

Lipid nanoparticles (LNPs) encapsulating nucleic acids lipid formulations that protect the cargo and facilitate cellular uptake through endocytosis. Once inside the cell, LNPs escape endosomes via lipid fusion, releasing their nucleic acids cargo into the cytoplasm for therapeutic mode of action. LNPs can also be engineered with specific ligands to enhance targeting of surface receptors of particular cell types, although non-specific uptake remains a challenge.

 

Challenges and Limitations of Sugar-Based Targeting and LNPs

Sugar targeting pitfalls:
The success of this strategy depends on the presence of sugar-binding receptors on target cells. Not all cell types express high levels of receptors, limiting the approach’s applicability to certain diseases (e.g., liver diseases or tumors with overexpressed receptors).
Short Half-Life of Natural Sugars:
Many naturally occurring sugars are rapidly degraded or removed from circulation, which can reduce the efficiency of delivery. This is being addressed through synthetic sugar derivatives and stabilizing formulations.

Toxicity:
While LNPs are generally well-tolerated, high doses can induce immune responses or liver toxicity.
Targeting and Off-Target Effects:
Although LNPs can encapsulate nucleic acids effectively, non-specific uptake in particular by immune cells can lead to off-target effects.
Delivery Efficiency:
Effective intracellular delivery, especially in non-liver tissues, remains a challenge. Enhancing endosomal escape mechanisms, so the LNP contents can reach the cytoplasm. continues to be a major research focus

 

Ongoing Research and Future Direction

Hybrid Systems:
Some studies are exploring combining sugar-based targeting with other targeting methods like antibodies, nanobodies, fatty acids etc. to create multi-targeting.
Tissue Targeting:
Developing sugar-conjugated oligonucleotides that can bind to specific receptors on the extracellular matrix or other components of tissues, facilitating more effective delivery.
Personalized Medicine:
LNP delivery method play a significant role in personalized treatments, particularly in oncology, where mRNA or siRNA can be tailored to a patient's specific tumor profile.
Systemic vs. Localized Delivery:
Researchers are exploring how to deliver LNPs systemically (through the bloodstream) or via local administration (e.g., directly into tumors or specific organs) to enhance therapeutic outcomes.

A major advantage of sugar targeting is the ability to administer higher doses of oligonucleotides. As no packaging material is required that could potentially cause unwanted immune reactions. This allows for a more specific and stronger immune response, which is particularly beneficial for therapy.

 

baseclick GmbH is a leader in the development of customised bioconjugation solutions and promotes multi-targeting strategies by offering high quality products such as GalNAc-DBCO, Tri-β-GalNAc-PEG3-Azide, Tri-Mannose and Oligo synthesis services.
This comprehensive approach empowers researchers to conjugate their Oligonucleotides independently using our products or collaborate with our experts via the Oligosynthesis service to design a fully customized sugar conjugated Oligos,  tailored to their specific needs. By offering both flexibility and expert support, baseclick aims to streamline the research process and drive innovation.

 

 

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