Targeting intestinal inflammation using locked nucleic acids delivered via lipid nanoparticles

Area of Science:

• Biotechnology
• Pharmacology
• Immunology

Background:

• Locked nucleic acids (LNAs) are advanced antisense oligonucleotides with high binding affinity.
• A key limitation of LNAs is the need for high dosages, potentially causing adverse effects.

Purpose of the Study:

• To investigate the use of lipid-based nanoparticles (LNPs) for delivering LNAs to treat intestinal inflammation.
• To assess the efficacy and safety of LNP-delivered LNAs in a mouse model.

Main Methods:

• Screened eight LNP formulations with novel ionizable lipids for stability and toxicity.
• Loaded LNPs with a splice-switcher sequence for in vitro potency assessment.
• Evaluated lead LNP candidates in vivo, including a formulation targeting Tumor necrosis factor alpha in a colitis model.

Main Results:

• LNP delivery achieved a 30-fold dose reduction for LNAs compared to unformulated oligonucleotides.
• The most potent LNP formulation significantly reduced disease severity and inflammatory cytokines in a mouse model of colitis.
• Demonstrated good safety profile for LNP-delivered LNA treatment.

Conclusions:

• Lipid nanoparticles enable precise and efficient delivery of locked nucleic acids.
• LNP-mediated LNA delivery shows significant promise for treating intestinal inflammation and other inflammatory diseases.
• This approach offers a potential strategy to overcome LNA dosage limitations and improve therapeutic outcomes.