Lipidation as a Driver of Spatial Organization and Function in Proteins and Nucleic Acids

Abstract Beyond serving as passive structural barriers, cellular membranes actively drive the spatial organization and compartmentalized function of macromolecules. Here, we review the interplay between lipid chemistry and lipidation-dependent spatial organization across both proteins and nucleic acids. This paradigm reflects a deep chemical continuity rooted in prebiotic evolution, where vesicles self-assembled from simple amphiphiles facilitate the membrane association of primitive polymers. In extant biology, highly regulated enzymatic lipidation serves as a critical determinant for membrane association, intracellular trafficking, and organization of the proteome. Synthetic lipid modification of nucleic acids transforms them into amphiphilic biomaterials with emergent properties spanning functional supramolecular assembly and systemic biodistribution, ultimately enabling advanced therapeutic modulation of gene expression.