Host Microenvironment Reprogramming by Saccharides Overcomes Lung Barriers for mRNA Therapeutics

Abstract Overcoming biological barriers remains the paramount challenge for pulmonary mRNA therapeutics. Conventional approaches focus exclusively on passively optimizing formulation quality without controlling dynamic host barriers. Here, we pioneer a host-centric strategy by leveraging sugar that actively reprograms the airway microenvironment to boost IVT-mRNA transfection. Utilizing machine learning-accelerated screening of a chemically diverse saccharide library, we identify D-glucose as the best-performing candidate. Glucose assisted-delivery within lipid nanoparticles (Glu-LNP) achieves robust, lung-specific protein expression (up to 131.21-fold increase) across diverse preclinical models with reduced inflammation. In lung carcinoma models, Glu-LNP-encapsulated IL-12 mRNA reduced tumor burden by approximately 59.12% and improved survival by 2.5-fold compared to the LNP group. Mechanistically, glucose orchestrates a dual-pathway cascade: metabolic reprogramming via the Warburg effect elevates ATP, fueling endocytosis and translation; ATP further activates the P2Y2-IP3 signaling axis that triggers Ca2 + release and subsequent CLCA1/TMEM16A-dependent chloride/bicarbonate efflux, which remodels mucus barriers and enhances nanoparticle penetration. This bioenergetic and mucolytic host intervention strategy presents a broadly applicable paradigm to transcend delivery limitations for respiratory mRNA therapeutics.