A study explores the use of piperidine-based ionizable lipids to enhance the thermostability of mRNA–lipid nanoparticle (LNP) systems. The research addresses the challenge of maintaining mRNA stability during long-term storage, particularly at refrigeration temperatures. The study demonstrates that piperidine-based lipids improve the long-term storage stability of mRNA/LNPs as liquid formulations. High-performance liquid chromatography analysis and additional lipid synthesis reveal that the amine moieties of ionizable lipids play a vital role in limiting reactive aldehyde generation, mRNA–lipid adduct formation, and loss of mRNA function during storage. These findings highlight the importance of lipid design in enhancing the shelf-life of mRNA/LNP systems. mRNA has gained increasing importance due to its ability to encode specific proteins and its potential for rapid development and production, as seen in mRNA-based vaccines against SARS-CoV-2. Lipid nanoparticles (LNPs) are widely used for in vivo mRNA delivery, protecting the mRNA from degradation and facilitating its delivery to target cells. LNPs typically consist of ionizable lipids, cholesterol, phospholipids, and PEG-conjugated lipids. Ionizable lipids contain a positively charged amino group that interacts with the negatively charged phosphate backbone of mRNA, playing a critical role in encapsulating the mRNA and promoting its escape from the endosome. The long-term storage of mRNA/LNP formulations remains a significant challenge. mRNA is inherently susceptible to degradation via hydrolytic cleavage and oxidation. LNPs and their components can undergo physical and chemical damage during storage, with these degradation processes accelerated by thermal stress. To mitigate these risks, mRNA/LNP formulations are stored at -20°C or below. However, cryogenic storage is costly and not ideal for widespread use. Lyophilization is a promising approach for improving the thermostability of mRNA/LNP. Reducing the amount of residual water in the LNP core decreases the risk of mRNA degradation, but it requires complex, lengthy, and high-energy processes. Additionally, the nanoparticles can be damaged and physicochemically changed by reconstitution, even in the presence of cryoprotectants. There is a growing demand for thermostable mRNA/LNPs that can be stored in liquid form. It is important to overcome the innate instability of mRNA along with the challenge of unintended addition reactions of lipid impurities with mRNA. Ionizable lipids with tertiary amines generate aldehyde impurities through oxidation and hydrolysis; these impurities covalently bind to mRNA, compromising its integrity and activity during storage. This mechanism decreases the thermostability of mRNA/LNP systems. The amine head of ionizable lipids is responsible for aldehyde generation; therefore, we hypothesized that the oxidation and hydrolysis of ionizable lipids and the resulting aldehyde generation could be limited by strategically designing the amine structure; this could enhance the long-term stability of mRNAA study explores the use of piperidine-based ionizable lipids to enhance the thermostability of mRNA–lipid nanoparticle (LNP) systems. The research addresses the challenge of maintaining mRNA stability during long-term storage, particularly at refrigeration temperatures. The study demonstrates that piperidine-based lipids improve the long-term storage stability of mRNA/LNPs as liquid formulations. High-performance liquid chromatography analysis and additional lipid synthesis reveal that the amine moieties of ionizable lipids play a vital role in limiting reactive aldehyde generation, mRNA–lipid adduct formation, and loss of mRNA function during storage. These findings highlight the importance of lipid design in enhancing the shelf-life of mRNA/LNP systems. mRNA has gained increasing importance due to its ability to encode specific proteins and its potential for rapid development and production, as seen in mRNA-based vaccines against SARS-CoV-2. Lipid nanoparticles (LNPs) are widely used for in vivo mRNA delivery, protecting the mRNA from degradation and facilitating its delivery to target cells. LNPs typically consist of ionizable lipids, cholesterol, phospholipids, and PEG-conjugated lipids. Ionizable lipids contain a positively charged amino group that interacts with the negatively charged phosphate backbone of mRNA, playing a critical role in encapsulating the mRNA and promoting its escape from the endosome. The long-term storage of mRNA/LNP formulations remains a significant challenge. mRNA is inherently susceptible to degradation via hydrolytic cleavage and oxidation. LNPs and their components can undergo physical and chemical damage during storage, with these degradation processes accelerated by thermal stress. To mitigate these risks, mRNA/LNP formulations are stored at -20°C or below. However, cryogenic storage is costly and not ideal for widespread use. Lyophilization is a promising approach for improving the thermostability of mRNA/LNP. Reducing the amount of residual water in the LNP core decreases the risk of mRNA degradation, but it requires complex, lengthy, and high-energy processes. Additionally, the nanoparticles can be damaged and physicochemically changed by reconstitution, even in the presence of cryoprotectants. There is a growing demand for thermostable mRNA/LNPs that can be stored in liquid form. It is important to overcome the innate instability of mRNA along with the challenge of unintended addition reactions of lipid impurities with mRNA. Ionizable lipids with tertiary amines generate aldehyde impurities through oxidation and hydrolysis; these impurities covalently bind to mRNA, compromising its integrity and activity during storage. This mechanism decreases the thermostability of mRNA/LNP systems. The amine head of ionizable lipids is responsible for aldehyde generation; therefore, we hypothesized that the oxidation and hydrolysis of ionizable lipids and the resulting aldehyde generation could be limited by strategically designing the amine structure; this could enhance the long-term stability of mRNA