Spatial Organization of Lipid Nanoparticle siRNA Delivery Systems Revealed by an Integrated Magnetic Resonance...

Area of Science:

• Biophysical Chemistry
• Materials Science
• Nanotechnology

Background:

• Lipid nanoparticles (LNPs) are vital for targeted drug delivery across various administration routes.
• Current microscopy techniques lack the resolution to detail the spatial arrangement of LNP components.
• Understanding LNP internal structure is critical for optimizing drug efficacy and safety.

Purpose of the Study:

• To develop and apply a novel multinuclear solid-state NMR approach for characterizing LNP internal structure.
• To determine the spatial organization of siRNA, targeting agents, and excipients within LNPs.
• To provide a structural model for siRNA-based LNPs used in clinical trials.

Main Methods:

• Utilized multinuclear solid-state magic-angle-spinning (MAS) NMR spectroscopy.
• Employed dynamic nuclear polarization (DNP) for enhanced sensitivity.
• Incorporated selective 2H labeling to detect low-concentration components like siRNA and targeting agents.

Main Results:

• Achieved high-resolution structural characterization of LNP constituents.
• Developed a structural model revealing siRNA localized in the core.
• Identified targeting agents positioned beneath the lipid bilayer surface and sugars on the exterior.

Conclusions:

• The presented multinuclear solid-state NMR (MAS NMR) approach enables detailed structural analysis of complex LNPs.
• This method provides crucial insights into the spatial organization of active ingredients and excipients.
• The technique is broadly applicable to other multi-component biological formulations for drug delivery.