Ionic liquid-coated lipid nanoparticles increase siRNA uptake into CNS targets

Area of Science:

• Biomaterials Science
• Nanotechnology
• Neuroscience

Background:

• Lipidoid nanoparticles (LNPs) are clinically used for nucleic acid delivery, primarily targeting liver and muscle.
• Post-administration, LNPs are naturally directed to the liver by plasma protein adsorption, notably apolipoprotein E.
• Targeting the central nervous system (CNS) remains a challenge due to biological barriers.

Purpose of the Study:

• To re-engineer LNPs using ionic liquids (ILs) to reduce plasma protein adsorption.
• To enhance LNP accumulation in challenging CNS targets like brain endothelial cells (BECs) and neurons.
• To explore ILs as tunable biomaterials for LNP surface modification.

Main Methods:

• Two LNP re-engineering approaches were developed using a choline trans-2-hexenoate IL.
• Approach 1: Optimized an IL-coating process on standard LNP formulations.
• Approach 2: Incorporated ILs into LNPs by replacing the PEG-lipid component.

Main Results:

• Both IL-coated and IL-incorporated LNPs exhibited colloidal stability and similar morphologies to standard LNPs.
• IL-coated LNPs demonstrated significantly reduced plasma protein adsorption compared to standard LNPs.
• IL-coated LNPs showed superior uptake in mouse BECs and neurons.

Conclusions:

• Re-engineering the LNP platform with ILs is feasible for delivering therapeutics to CNS targets.
• LNP surface properties critically influence their affinity and uptake into hard-to-deliver cell types.
• This strategy holds promise for advancing CNS drug delivery applications.