A Nature Biotechnology study deployed advanced biophysical analyses to resolve the structural properties that determine lipid nanoparticle (LNP) performance for RNA delivery. The paper provides guidance to optimize formulation variables and manufacturing parameters that influence payload encapsulation, stability and endosomal escape. Using complementary techniques — cryo‑EM, scattering methods and functional assays — investigators linked specific lipid composition and particle architecture to transfection efficiency and in vivo biodistribution. The work creates an evidence base for iterative LNP design beyond empirical screens. For mRNA and siRNA developers, the study offers actionable formulation principles that could reduce failure rates and accelerate clinical translation by aligning physicochemical design with delivery and pharmacology targets.