Hypothesis: Anionic surfactants can form stable monolayers around oil droplets via interactions with macromolecules thereby physically stabilizing high fish oil enriched emulsions (50-70% fish oil) while phenolic acids have antioxidant properties to prevent lipid oxidation. COSMO-RS (Conductor-like Screening Model for Real Solvents) is a powerful tool for the rational design of molecules with multi-functionalities. Therefore, it should be possible to assemble segments of natural molecules into a single multifunctional molecule using COSMO-RS to confer both physical and oxidative stability to fish oil enriched systems. Experiments: COSMO-RS was used to predict the thermodynamic properties of series phenoleoyl malic acid esters of monoglycerides in comparison with commercial emulsifiers. A novel series of amphiphilic lipids, equipped with multi-functional groups from natural building blocks (fatty-acyl, glycerol, malic & phenolic acids), were then synthesized in a facile approach and characterized by various spectroscopy techniques. Oil-in-water emulsions stabilized by the amphiphilic lipids were formulated and characterized by dynamic light scattering measurements and fluorescence imaging. Findings: An elaborate integration of multi-functions into a single molecule was achieved, displaying superior or comparable emulsion stability and antioxidant property, compared to a commercial emulsifier, phenolic acids and their combinations. This is the first report to holistically integrate the rational design, synthesis and functional characterization of natural-based multifunctional molecules for high capacity fish oil delivery systems. (C) 2017 Elsevier Inc. All rights reserved.