Inhalable Dry Powders for Lung mRNA Delivery

Area of Science:

• Biotechnology
• Pulmonary Drug Delivery
• Nanomedicine

Background:

• Messenger RNA (mRNA) therapeutics show promise but face challenges in lung delivery.
• Direct intratracheal instillation of liquid mRNA formulations raises safety and distribution concerns in humans.
• Inhalable formulations are needed for safe and effective mRNA delivery to the lung.

Purpose of the Study:

• To develop stable, inhalable dry powder formulations of lipid nanoparticles for mRNA delivery to the lung.
• To evaluate the aerosolization properties and pulmonary mRNA delivery efficiency of these dry powder formulations.
• To assess the compatibility of the developed formulations with various ionizable lipids.

Main Methods:

• Spray-freeze-drying was employed to create dry powder lipid nanoparticle formulations.
• Aerosolization properties were characterized by measuring mean mass aerodynamic diameter (MMAD) and fine particle fraction (FPF).
• In vivo pulmonary mRNA delivery was assessed for different ionizable lipid-based formulations.

Main Results:

• Dry powder formulations exhibited suitable aerosolization properties (MMAD 3-4 microns, FPF ≈40%) for deep lung delivery.
• Four different ionizable lipid-based formulations were successfully prepared as inhalable dry powders.
• All evaluated dry powder formulations demonstrated in vivo pulmonary mRNA delivery comparable to liquid formulations.

Conclusions:

• Spray-freeze-dried lipid nanoparticle dry powders represent a promising platform for inhalable mRNA therapeutics.
• The developed formulations are robust, biologically active, and compatible with various ionizable lipids.
• This work paves the way for the clinical development of inhaled mRNA dry powder therapies for lung diseases.