| Summary: | Due to the increase in life expectancy, promoting active aging is a crucial challenge for the 21st century. Therefore, searching for new neuroprotective drugs is urgent, and marine macroalgae are considered excellent sources of structurally diverse bioactive molecules with recognized pharmaceutical and biomedical potential. Aiming to contribute to finding new neuroprotective drugs, a multi-step subcritical water extraction (SWE) process was applied to the green macroalga <i>Codium tomentosum</i> using a gradient of temperatures (from room temperature to 250 °C). Four fractions were obtained and fraction F4 (obtained in the range of 190–250 °C) was the most active against oxidative stress and enzymes linked to neurodegeneration and major depression. Therefore, phytosomes were prepared with F4 for a future food application. A Box–Behnken design with three independent variables was applied and the phytosomes prepared using the optimal conditions were further modified with DSPE-PEG (2000)-maleimide and APoE and characterized by dynamic light scattering (DLS), UV spectrophotometry, octanol–water partition coefficient (Kow), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). Results demonstrated that the complex was successfully formed and displayed low particle size and high octanol–water partition coefficient.
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