<p>The aim of this study was to evaluate the potential of mixed dry reverse micelles (dRMs) to increase the lipophilicity of therapeutic proteins and allow their incorporation into self-emulsifying drug delivery systems (SEDDS). Horseradish peroxidase (HRP) was incorporated in mixed dRMs, forming HRP-dRMs, using soybean phosphatidylcholine (SPC) and sodium docusate (SD) as surfactants. HRP-dRMs were characterized with respect to their distribution coefficient and stability in simulated physiological fluids. Moreover, HRP-dRMs were loaded in SEDDS, which were characterized for their payload, stability, distribution coefficients between the lipophilic phase of SEDDS and release medium and their ability to protect the incorporated protein towards enzymatic degradation in aqueous media containing trypsin and chymotrypsin. The synergistic effect of two surfactants to form dRMs led to a payload of 3% (w/v) for the model protein in a lipophilic phase without the use of organic cosolvents. Moreover, the HRP-dRMs incorporation increased the LogD _{n−octanol/water} value of HRP from − 3.36 to 3.10. This increment in lipophilicity provided a higher retention of the protein within the oily droplets, and correled with enzymatic degradation studies, where &gt; 95% of the incorporated protein remained intact. This study provided first evidence for unprecedented amount of a model protein of high molecular weight loaded in SEDDS through dRMs incorporation as a possible tool for their oral delivery, with a 15-fold increment compared to the previously achieved results.</p> Graphical abstract <p></p>