Conformation-sensitive targeting of lipid nanoparticles for RNA therapeutics

Area of Science:

• Biomedical Engineering
• Immunology
• Gene Therapy

Background:

• Effective in vivo gene expression modulation requires non-immunogenic delivery vehicles.
• Lipid nanoparticles (LNPs) are advanced non-viral nucleic-acid delivery systems but primarily accumulate in liver cells.
• Enhanced delivery to non-liver cell types is crucial for broader therapeutic applications.

Purpose of the Study:

• To develop a conformation-sensitive targeting strategy for in vivo gene silencing in specific leukocyte subsets.
• To evaluate the therapeutic potential of targeted LNPs in a murine model of colitis.
• To assess the safety profile of these targeted LNPs regarding immune activation and liver toxicity.

Main Methods:

• Utilized a conformation-sensitive targeting strategy to direct LNPs.
• Targeted the high-affinity conformation of α4β7 integrin on inflammatory gut-homing leukocytes.
• Administered targeted LNPs intravenously to mice with experimental colitis.

Main Results:

• Achieved in vivo gene silencing of interferon-γ in the gut.
• Demonstrated improved therapeutic outcomes in experimental colitis.
• Observed no adverse immune activation or liver toxicity associated with the LNPs.

Conclusions:

• Conformation-sensitive targeting of LNPs enables selective gene silencing in specific leukocyte populations.
• Targeted delivery to α4β7 integrin-expressing leukocytes offers a promising therapeutic strategy for inflammatory gut diseases.
• This LNP targeting approach may be adaptable for delivering payloads to other conformation-sensitive targets.