This study investigates the challenges of maintaining the thermostability of mRNA/LNP systems and proposes a solution by engineering piperidine-based ionizable lipids. The research highlights the importance of lipid design in enhancing the shelf-life of mRNA/LNP systems. The study demonstrates that piperidine-based lipids improve the long-term storage stability of mRNA/LNPs at refrigeration temperatures as liquid formulations. High-performance liquid chromatography analysis and lipid synthesis reveal that amine moieties in ionizable lipids play a crucial role in limiting reactive aldehyde generation, mRNA-lipid adduct formation, and loss of mRNA function during storage. The findings suggest that the amine structure of ionizable lipids is essential for controlling aldehyde impurity generation and enhancing the stability of mRNA/LNPs at higher temperatures. The study also shows that piperidine-based lipids can maintain mRNA/LNP activity even after refrigerated storage, providing promising insights into improving the shelf-life of mRNA/LNP-based therapeutics.This study investigates the challenges of maintaining the thermostability of mRNA/LNP systems and proposes a solution by engineering piperidine-based ionizable lipids. The research highlights the importance of lipid design in enhancing the shelf-life of mRNA/LNP systems. The study demonstrates that piperidine-based lipids improve the long-term storage stability of mRNA/LNPs at refrigeration temperatures as liquid formulations. High-performance liquid chromatography analysis and lipid synthesis reveal that amine moieties in ionizable lipids play a crucial role in limiting reactive aldehyde generation, mRNA-lipid adduct formation, and loss of mRNA function during storage. The findings suggest that the amine structure of ionizable lipids is essential for controlling aldehyde impurity generation and enhancing the stability of mRNA/LNPs at higher temperatures. The study also shows that piperidine-based lipids can maintain mRNA/LNP activity even after refrigerated storage, providing promising insights into improving the shelf-life of mRNA/LNP-based therapeutics.