Lipid nanoparticles (LNPs) are the most established and clinically advanced platform for RNA delivery. While significant efforts have been made to improve RNA delivery efficiency for improved protein production, the interplay between physiological stability, target specificity, and therapeutic efficacy of RNA-LNPs remains largely unexplored. This review highlights the crucial, yet often overlooked, impact of in vivo stability or instability of RNA-LNPs in contact with biological fluids on delivery performance. We discuss the various factors, including lipid composition, particle surface properties and interactions with proteins in physiological conditions, and provide an overview of the current methods for assessing RNA-LNP stability in biological fluids, such as dynamic laser light scattering, liquid chromatography, and fluorescent and radiolabeled techniques. In the final part, we propose strategies for enhancing stability, with a focus on shielding lipids. Therefore, this work highlights the importance of investigating and understanding the balance between stability and instability of LNPs in the biological context to achieve a more meaningful correlation between formulation properties and in vivo performance.