Effect of Low Glucose on mRNA Delivery Efficiency via Lipid Nanoparticles and Its Underlying Mechanisms

mRNA therapy has shown great potential in vaccine development, cancer treatment, and the treatment of rare diseases. Lipid nanoparticles (LNPs) are key delivery carriers that are essential to the success of mRNA therapy. Here, we found that a low-glucose microenvironment affected the efficiency of LNP-mediated mRNA delivery. Two LNPs (ALC-0315@LNP and SM-102@LNP) were tested in three types of cells under different glucose conditions. The results showed that low-glucose levels significantly reduced the translation of LNP-delivered mRNA into protein, and this negative effect was reversible upon the restoration of glucose levels. A mouse tumor model further confirmed that hypoglycemia diminished the <i>in vivo</i> mRNA delivery efficiency of LNPs. Further mechanistic studies revealed that the reduced efficiency was not due to impaired cellular uptake or lysosomal escape of LNPs, but rather to disrupted glucose energy metabolism. Under low-glucose conditions, cellular ATP and GTP levels were reduced, directly inhibiting the mRNA translation process, which is dependent on these high-energy molecules. This study systematically revealed for the first time that low-glucose conditions reduced mRNA-LNP delivery efficiency by impairing cellular energy metabolism. These findings provide insights for designing metabolic-microenvironment-adapted mRNA therapies and offer strategies to improve mRNA therapy efficacy in treating ischemic stroke and cancer patients.