Manufacturing mRNA-Loaded Lipid Nanoparticles with Precise Size and Morphology Control

Area of Science:

• Biotechnology
• Materials Science
• Pharmaceutical Sciences

Background:

• Lipid nanoparticles (LNPs) are crucial for delivering nucleic acid therapeutics.
• Current LNP production methods often oversimplify self-assembly into a single mixing step, limiting control over LNP properties.
• The relationship between process inputs and LNP characteristics remains poorly understood in conventional manufacturing.

Purpose of the Study:

• To develop a method for producing mRNA-loaded LNPs with independent and predictive control over size and morphology.
• To decouple LNP particle design from mixing parameters and formulation adjustments.
• To enable the rational engineering of LNPs with specific, desired properties.

Main Methods:

• Utilized mixing under high fusogenicity conditions by modulating solvent composition.
• Employed timed post-injection of an aqueous buffer to kinetically arrest LNPs.
• Demonstrated the method using benchmark LNP formulations in an impinging jet mixer.

Main Results:

• Achieved independent and predictive control over LNP size and morphology.
• Produced LNPs with up to an 8-fold increase in in vitro transfection efficacy compared to conventional methods.
• Maintained other essential quality attributes without compromise.

Conclusions:

• The presented method allows for rational engineering of LNPs with defined properties.
• This approach facilitates enhanced quality control, predictive modeling, and rational process translation for LNP manufacturing.
• The findings pave the way for more effective nucleic acid therapeutics delivery systems.