Antisense Oligonucleotides (ASOs) are among the fastest-growing classes of therapeutics used to modulate gene expression. Among ASOs, Locked Nucleic Acids (LNAs) are an advanced form of ASO with chemical modifications that enhance their binding affinity and stability ⁽¹⁾. As of today, several ASOs have been approved for clinical use, primarily for the treatment of rare genetic diseases and neurological disorders. However, a significant hurdle to their use is the need for a high dose to achieve a therapeutic effect, which often leads to an unfavorable risk-benefit profile.

We hypothesized that encapsulating ASOs in Lipid Nanoparticles (LNPs) with defined tropism would enhance their delivery to the target organ, improve therapeutic efficacy, and reduce the required dose. We recently discovered an LNP formulation with passive tropism for the gastrointestinal tract. We demonstrated its efficacy in delivering therapeutic mRNA to the colon in an inflammatory bowel disease (IBD) mouse model ⁽²⁾. Herein, novel ionizable lipids from our proprietary library ⁽³⁾ were used to generate gastrointestinal-oriented LNP formulations, carrying ASO payload. To this end, we selected ASOs specifically targeting Tumor Necrosis Factor-α and demonstrated improved therapeutic outcomes in an IBD mouse model using LNPs as delivery vehicles. Furthermore, a 30-fold dose reduction was observed compared with non-LNP, free ASOs, without any safety concerns  ⁽⁴⁾.

This work highlights how the encapsulation of ASOs in LNPs will expand their therapeutic window and improve the safety profile of systemic ASOs administration, primarily by reducing the required dose and enabling more precise delivery. This could open new therapeutic avenues for ASOs for the treatment of inflammatory and other diseases.

UNMET NEED
One of the main hurdles preventing ASOs from wider therapeutic use is the lack of specific delivery. Due to the non-specific nature of their biodistribution, high doses are required to achieve the desired therapeutic effects in the target organ. At the same time, much of the injected material is accumulated in the liver and the spleen, which may lead to toxicity. To achieve broader use in treating various diseases, the biodistribution of ASOs needs to be more precise, thereby lowering the required dose.

OUR SOLUTION
Encapsulating therapeutic ASOs in a passively targeting LNP delivery system will protect them and mediate their accumulation at the desired site post-systemic administration. Consequently, the administered dose of ASOs and the incidence of non-specific adverse effects will be reduced, while the therapeutic effect is maintained or even enhanced.

APPLICATIONS
Our study demonstrates the in vivo efficacy of LNPs as ASO carriers, leading them to the inflamed gut. Given the diversity of passively targeting LNPs we explored, which include both the inflamed gut, liver, spleen and the lungs, and when adding the various options for active cell-specific targeting agents, many avenues, such as targeting other organs (e.g., lungs, bone marrow) and targeting specific cell populations (such as subset of immune cells⁽³⁾), can be explored.

MARKET/ POTENTIAL MARKET
The clinical pipeline for ASOs and LNA-modified ASOs is very active, moving beyond rare diseases into common conditions, cancer, infectious, inflammatory, and neurodegenerative diseases.

STATUS
In vivo PoC and PoT (Proof of Technology) were shown and published.

INTELLECTUAL PROPERTY
Several patents/patent applications protected this technology.

REFERENCES
1. Qassem S, Breier D, Naidu GS, Hazan-Halevy I, Peer D. Unlocking the therapeutic potential of locked nucleic acids through lipid nanoparticle delivery. Mol Ther Nucleic Acids. 2024;35(2):102224.
2. Rampado R, Naidu GS, Karpov O, Goldsmith M, Sharma P, Ezra A, et al. Lipid Nanoparticles With Fine-Tuned Composition Show Enhanced Colon Targeting as a Platform for mRNA Therapeutics. Adv Sci (Weinh). 2025;12(3):e2408744.
3. Naidu GS, Yong SB, Ramishetti S, Rampado R, Sharma P, Ezra A, et al. A Combinatorial Library of Lipid Nanoparticles for Cell Type-Specific mRNA Delivery. Adv Sci (Weinh). 2023;10(19):e2301929.
4. Qassem S, Naidu GS, Goldsmith M, Breier D, Rampado R, Ramishetti S, et al. Targeting intestinal inflammation using locked nucleic acids delivered via lipid nanoparticles. Nat Commun. 2025;16(1):7682.