Hypothesis: Simple zwitterions used as auxiliary agents might have the potential to change the zeta potential of oil-in-water (o/w) nanoemulsions on the mucosa. Experiments: The zwitterion phosphorylated tyramine (p-Tyr) was synthesized by phosphorylation of Boc-tyramine (Boc-Tyr) using phosphoryl chloride (POCl3). It was incorporated with 2% (m/v) in a self emulsifying lipophilic phase comprising Captex 35, Cremophor EL, Capmul MCM and glycerol 85 at a ratio of 30:30:30:10 v/v. Phosphate release and resulting change in zeta potential were evaluated by incubating p-Tyr containing nanoemulsion with isolated intestinal alkaline phosphatase (AP). Mucus permeating behavior was evaluated across mucus obtained from porcine small intestinal mucosa. Subsequently, cellular uptake studies were accomplished on Caco-2 cells. Findings: The p-Tyr loaded nanoemulsion exhibited a mean droplet size of 43 1.7 nm and zeta potential of -8.40 mV. Phosphate moieties were rapidly cleaved from p-Tyr loaded nanoemulsions after incubation with isolated AP resulting in a shift in zeta potential from -8.40 mV to +1.2 mV. p-Tyr loaded nanoemulsion revealed a significantly (p <= 0.001) improved mucus permeation compared to the same nanoemulsion having been pre-treated with AP. Cellular uptake of the zeta potential changing oily droplets was 2.4-fold improved. Phosphorylated zwitterions seem to be an alternative to cationic surfactants and considered as promising auxiliary agents for zeta potential changing nanoemulsions. (C) 2020 The Authors. Published by Elsevier Inc.