Lipid digestion- driven drug fate as a key determinant of SNEDDS performance: Mechanistic basis of absorption and in vitro- in vivo disconnect.

Self-nanoemulsifying drug delivery systems (SNEDDS) represent a major class of lipid-based nanomedicines that are primarily utilised for the enhancement of oral delivery of poorly water-soluble drugs. However, their clinical translation remains inconsistent due to a sustained divergence between in vitro performance and in vivo bioavailability. Although substantial literature exists, a unified mechanistic framework linking these outcomes is still seen to be lacking. This review critically examines the underlying causes of the translational gap, emphasising identifying key limitations in current evaluation strategies and the misalignment between standard formulation metrics and processes relevant to absorption. It reconceptualises SNEDDS as a dynamic, digestion-mediated system in which drug fate is dictated by time-dependent interactions between lipid transformation, drug redistribution, and physiological variability. Particular focus is given to the underexplored determinants, including supersaturation persistence, post-digestion drug redistribution, and constraints in lymphatic transport. A predictive, mechanism-based design framework is proposed linking drug properties, lipid behaviour, and physiological constraints together. Future directions highlight the potential of adaptive in vitro systems, multi-scale modelling, and artificial intelligence-driven optimisation to ensure more reliable, context-aware SNEDDS development and also improved clinical translation.