On the Influence of Nucleic Acid Backbone Modifications on Lipid Nanoparticle Morphology

Area of Science:

• Biotechnology
• Drug Delivery
• Molecular Biology

Background:

• Nucleic acid therapeutics offer a promising approach for disease treatment by targeting disease at its source.
• Nucleic acids face challenges like degradation by serum nucleases, immune clearance, and instability in biological media.
• Chemical modifications and lipid nanoparticles (LNPs) are employed to enhance nucleic acid stability and delivery.

Purpose of the Study:

• To investigate the impact of chemical modifications on nucleic acid-LNP interactions and morphology.
• To challenge the assumption that chemical modifications do not affect LNP delivery.
• To elucidate the role of specific chemical modifications in LNP formulation and entrapment efficiency.

Main Methods:

• Synthesis and characterization of modified nucleic acids.
• Formulation of lipid nanoparticles (LNPs) with chemically modified nucleic acids.
• Analysis of LNP morphology and nucleic acid entrapment using biophysical techniques.

Main Results:

• Chemical modifications to the nucleic acid backbone substantially alter LNP morphology.
• Phosphorothioate modifications demonstrate stronger interactions with ionizable amino lipids compared to other modifications.
• Enhanced entrapment of nucleic acids within LNPs was observed with phosphorothioate modifications.

Conclusions:

• Chemical modifications are critical factors influencing LNP formation, morphology, and drug delivery efficiency.
• Understanding these interactions is key to optimizing LNP-based nucleic acid therapeutics.
• This study provides foundational insights into the interplay between nucleic acid chemistry and LNP formulation.