Lipid nanoparticles have been widely utilized as effective non-viral delivery platforms for various nucleic acid therapeutics. However, due to their thermal and physical instability, cryoprotectants are essential to maintain stability during storage and transportation. In this study, we applied macromolecular stabilizers as alternatives to the commonly used sucrose. Our results demonstrate that macromolecular stabilizers provide enhanced protection against structural instability, resulting in improved functional stability. Overall, macromolecular stabilizers are promising alternatives to sucrose for the storage and practical application of lipid nanoparticles.