Spray-dried RNA-lipid nanoparticle dry powder technology for stable and inhalable delivery of therapeutics

Background

Messenger RNA (mRNA) therapeutics have rapidly emerged as a transformative method for vaccination and gene therapy. However, the field faces significant hurdles related to the instability of mRNA molecules, which are highly susceptible to enzymatic degradation. Lipid nanoparticles (LNPs) have become the delivery vehicle of choice, shielding mRNA from degradation and facilitating cellular uptake.

Despite these advances, mRNA-LNP therapeutics is hindered by the need for ultracold storage and distribution. Pulmonary delivery via dry powder inhalers (DPIs) represents an alternative, offering improved patient compliance, portability, and the potential for direct treatment of respiratory diseases. Traditional methods such as lyophilization and spray drying can improve storage stability by removing water, but these processes often subject the nanoparticles to heat and shear stresses that can damage their structure.

Maintaining the delicate balance of particle size, encapsulation efficiency, and dispersibility after drying has proven difficult, with many formulations experiencing aggregation, loss of RNA integrity, or reduced bioactivity. In addition, the use of certain excipients or solvents, and suboptimal lipid compositions, have resulted in inconsistent outcomes. These limitations underscore the need for new formulation strategies that can reliably produce stable, inhalable RNA-LNP powders without compromising their therapeutic potential.

Technology description

This technology is a novel spray-dried RNA-lipid nanoparticle (RNA-LNP) dry powder optimized for therapeutic pulmonary delivery. It features a carefully engineered combination of trehalose and L-leucine as stabilizing excipients, alongside a lipid nanoparticle composition of MC3, cholesterol, DSPC, and PEG2000K.

A critical aspect of the process is the exclusion of ethanol from the feed solution, which preserves the integrity of the nanoparticles. The spray drying process is fine-tuned to maintain the RNA-LNP’s particle size, polydispersity index, and RNA encapsulation efficiency even at higher RNA loadings. The resulting dry powders are highly stable, easily reconstituted, and specifically designed for administration via dry powder inhalers, offering improved storage and handling compared to conventional liquid RNA-LNP formulations.

Unlike prior art that struggled with increased particle size, low encapsulation efficiency, or poor stability after spray drying, this approach consistently preserves the physical and functional properties of RNA-LNPs. The use of trehalose and L-leucine, the specific lipid ratios, and the avoidance of ethanol are all distinct choices that contribute to the superior stability and flexibility of the formulation. Additionally, the process allows for scalable production and higher RNA loading without compromising quality, making it suitable for a wide range of RNA-based therapeutics and other temperature-sensitive biologics. This positions the technology as a transformative solution for pulmonary delivery of RNA medicines, with significant advantages in storage, transport, and patient compliance.

Benefits

Enhanced storage stability of RNA-lipid nanoparticles
Maintains key physical properties post spray drying
Enables therapeutic pulmonary delivery via dry powder inhalers
Formulation flexibility allowing increased RNA loading
Scalable and cost-effective production process
Avoidance of ethanol in the feed solution
Potential applicability beyond RNA-LNPs to other temperature-sensitive biologics

Commercial applications

Inhalable mRNA vaccines
Pulmonary gene therapy delivery
Inhaled siRNA therapeutics
Dry powder CRISPR drug delivery
Inhalable monoclonal antibody treatments

Additional information

This technology describes spray-dried RNA-lipid nanoparticle dry powders for pulmonary delivery. It employs trehalose and L-leucine excipients with a specific LNP composition (MC3, cholesterol, DSPC, PEG2000K). Crucially, ethanol is avoided in the feed solution. This formulation maintains particle size, polydispersity, and RNA encapsulation efficiency after drying, enabling enhanced storage stability and suitability for dry powder inhalers.