Spray‐Dried mRNA‐LNP Powder Enabling Multi‐Route Delivery With 3‐Year Refrigerated Stability

The clinical translation of mRNA-lipid nanoparticle (mRNA-LNP) therapeutics is constrained by limited stability of liquid formulations, necessitating ultra-cold storage and restricting global accessibility. Here, we report a spray-dried dry powder platform for mRNA-LNPs that overcomes these limitations while enabling flexible routes of administration. Systematic evaluation of pharmaceutically relevant sugars identifies trehalose as an optimal matrix former, yielding high-recovery mRNA-LNP dry powder product (DPP) with controlled particle size, low residual moisture, and preserved LNP physicochemical properties upon reconstitution. Mechanistic studies combining solid-state characterization, fluorescence tracking, and solvent extraction demonstrate that mRNA-LNPs are entrapped within an amorphous trehalose matrix core, providing protection against dehydration and rehydration stress. Reconstituted DPP (RDPP) maintains in vivo protein expression comparable to liquid control (LC) following intravenous and intramuscular administration, while supporting effective mucosal delivery via pulmonary and sublingual routes. Direct administration of DPP without reconstitution enables lung-targeted protein expression, highlighting potential for cold-chain-independent therapies. Critically, DPP preserves colloidal stability, mRNA integrity, ionizable lipid stability, and biological activity for over 3 years under refrigerated conditions, whereas liquid formulation exhibits substantial degradation within 6-9 months. These findings establish spray-dried mRNA-LNP DPPs as a robust platform integrating long-term stability with multi-route delivery for improved accessibility of mRNA therapeutics.