A New Era in RNA Therapies

The Problem

RNA-based therapeutics are transforming modern medicine, providing powerful tools for targeted gene silencing and protein expression. However, successful clinical application depends heavily on efficient and specific RNA delivery. While lipid nanoparticles (LNPs) remain the standard, they often lack cell specificity and can cause side effects.

The Solution

At baseclick, we are advancing a new generation of cell targeted RNA delivery technologies that go beyond LNPs. Our engineered platform is based on glycoconjugation for attachment of carbohydrates such as GalNAc, tri-mannose, glucose, fucose,… – to enable receptor mediated uptake into specific cell types. These natural sugar ligands offer high specificity and biocompatibility and have already demonstrated clinical success as seen in FDA approved siRNA therapies such as GIVLAARI® (givosiran) and OXLUMO® (lumasiran), both of which use trivalent GalNAc conjugates for liver targeted delivery.

In addition to GalNAc, our modular system incorporates trimannose ligands for macrophage targeting, fatty acid conjugates (e.g. anandamide) and folate modifications, enabling highly customized solutions for RNA delivery. By exploiting ligand receptor interactions, these conjugates ensure improved biodistribution, reduced off-target effects and enhanced therapeutic efficacy. All without the limitations of encapsulation based systems.

The Outcome

Our delivery platform is ideal for companies seeking to develop cell specific RNA therapeutics from early discovery through to clinical application. Whether you’re targeting hepatocytes, immune cells or tumour cells, baseclick offers innovative tools to meet your delivery needs.

We have been at the forefront of click chemistry since its early invention, and our name reflects this deep-rooted expertise. Our robust and reliable click-based solutions are used worldwide for efficient and selective bioconjugation of nucleic acids. However, our capabilities go far beyond click chemistry. As RNA delivery evolves, so does the need for diverse conjugation strategies. We support a broad range of bifunctional linkers, enabling combinations such as click based attachment on one end and orthogonal chemistries, including NHS-esters, and many more. This flexibility allows us to address complex molecular designs and customized delivery solutions across therapeutic and diagnostic applications.

With this expanded toolbox, we empower our partners to develop next-generation RNA conjugates tailored to their specific needs. Whether it’s cell targeted delivery, in vivo stability, or controlled release.

Sugar Ligands for Precision Cell Targeting

Naked oligonucleotides face hurdles compared to small molecules such as high molecular weight, negative charge and susceptibility to nucleases, leading to poor cellular uptake and potential off-target effects. The stability issue was overcome by incorporating of modified nucleotides in the RNA molecules. Attaching carbohydrates, especially in cluster forms, to oligonucleotides can facilitate receptor-mediated endocytosis, thereby improving targeted delivery. Sugar ligands provide a natural and highly efficient approach to targeted RNA delivery.

• GalNAc conjugates: Trivalent N-acetyl-D-galactosamine (GalNAc) ligands bind specifically to ASGPR receptors on hepatocytes, enabling highly efficient liver-specific RNA delivery, as exemplified by the FDA-approved siRNA drug LEQVIO® (inclisiran) or ALN-TTRSC (revusiran).
• Mannose conjugates: D-mannose ligands target the CD206 receptor on macrophages. Multivalent mannose conjugates such as trimannose enhance uptake and gene silencing efficacy, although excessive valency may reduce efficacy.
• Optimized selectivity: Minimize off-target effects and reduce dose requirements for improved therapeutic efficacy.

The nature, valency and linker chemistry of carbohydrate conjugates are critical to optimizing delivery and minimizing off-target effects. Our modular conjugation platform allows these ligands to be seamlessly combined with other conjugates, redefining RNA delivery beyond LNPs.

Beyond Sugars: Fatty Acid, Folate Conjugates and Peptides

Expanding the possibilities of RNA targeting, our technology integrates fatty acid-based, folate and peptide conjugates:

• Anandamide (AEA): Fatty acid-based targeting demonstrated in PBMC cell lines and mouse hippocampal neurons.
• Folate conjugates: Exploiting folate receptor expression to target HeLa cells and macrophages.
• Peptide conjugates: Custom ligand options for enhanced cellular uptake and specificity.

By tailoring ligand selection to your target cells, we offer unparalleled flexibility in the design of next-generation RNA therapeutics.

Modular Linker Chemistry for Custom Conjugates

Our linker technology allows complete customization of RNA conjugates to ensure optimal stability, solubility and release profiles:

• PEG Linkers: Enhance solubility and bioavailability.
• Carbon linkers: Increase stability and reduce degradation.
• Cleavable linkers: Precisely control RNA release within target cells.

Compatible with a wide range of targeting ligands, our linker chemistry ensures highly efficient conjugation for superior therapeutic performance.

Click Chemistry: Copper & Copper-Free Strategies

Click chemistry enables seamless conjugation of targeting ligands to mRNA, siRNA and oligonucleotides, offering both copper-based and copper-free approaches:

• Copper catalyzed Click Chemistry: Validated in marketed drugs such as Trodelvy® (sacituzumab govitecan).
• Copper-free SPAAC Click Chemistry: Ideal for biocompatible applications in RNA therapeutics.

With highly selective and efficient reaction pathways, Click Chemistry is a key enabler in RNA drug development.