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Targeting intestinal inflammation using locked nucleic acids delivered via lipid nanoparticles

Year: 2025

Type: article

Abstract: Locked nucleic acids are a third-generation antisense oligonucleotides with high binding affinity. A major limitation is the high dosages they require to achieve efficacy which may induce unwanted adverse effects. Here, we report the use of Lipid-based nanoparticles to deliver locked nucleic acids for treating intestinal inflammation in mice. Eight formulations with novel ionizable lipids were screened for stability and toxicity. Particles were loaded with splice-switcher sequence, enabling a precise assessment of potency in vitro. Three lead candidates were tested in vivo, demonstrating a 30-fold dose reduction compared to the unformulated oligonucleotides. The most potent formulation, encapsulating a sequence against Tumor necrosis factor alpha, was evaluated in a mouse model of colitis. Treatment reduced disease severity and inflammatory cytokines, with good safety. These findings support the use of lipid nanoparticles for the precise delivery of locked nucleic acids and highlight their promise for future therapies. Locked nucleic acids have high binding and utility but currently suffer from off target effects due to the high does needed. Here, the authors show lipid nanoparticles can safely and effectively deliver locked nucleic acids to inflamed tissue in the gut, reducing the required dose and improving therapeutic outcomes in IBD.

Source: Nature Communications

DOI: 10.1038/s41467-025-63037-6