Development of an Inhalable Dry Powder Platform for mRNA Therapeutics

Messenger RNA (mRNA) therapeutics represent a groundbreaking approach in medicine, offering precise and personalized treatments by leveraging the patient's own cells to produce therapeutic proteins. However, mRNA is vulnerable to degradation by nucleases and environmental factors, emphasizing the need for innovative delivery strategies. This is especially critical in remote areas where maintaining challenging storage conditions can be difficult and access to healthcare personnel may be limited.

Therefore, this study aimed to develop an inhalable dry powder platform for mRNA therapeutics, integrating protection, efficient transfection, and favourable aerodynamic performance. Liposomes were formulated from DOTAP and DOPE lipids, encapsulating mRNA to form lipoplexes. Subsequently, a spray drying process was employed to produce inhalable microparticles embedding lipoplexes within a matrix, ensuring the preservation of mRNA activity.

Among the matrix materials investigated, mannitol demonstrated successful transfection efficiency and desirable aerodynamic characteristics. Nonetheless, challenges persisted, notably the presence of significant powder residue in capsule-based inhalers. To address this challenge, two optimisation strategies were implemented. The addition of L-leucine to the mRNA lipoplex dispersion proved effective in reducing powder residue in capsules and notably improved aerodynamic performance.

In summary, this study has established a comprehensive process from mRNA encapsulation to the production of an inhalable powder with tailored properties. Through systematic development, it has provided a proof of concept and laid the groundwork for the focused advancement of an inhalable dry powder platform for mRNA therapeutics.

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