Novel resveratrol-loaded core-shell nanoparticles, which comprise hydrophobically functionalized polyelectrolyte (HF-PE) shells and poly(ethylene succinate) (PES)/poly(lactide-co-glycolide) (PLGA) cores, were prepared using a fully scalable membrane-assisted approach. The process parameters, including the shear rates, fluxes, pore diameters and particular component concentrations, have been carefully studied in the field of their influence on the nanoproduct quality and features. The performed studies include both theoretical (calculation of the solubility and miscibility parameters; estimation of thermal properties using the group increment method) and experimental (complex colloidal and physicochemical characterization of core-shell nanocarriers with an impact on their phase structure) in vitro release profiles and morphology. The careful analysis of the nanocarriers’ thermal behavior by thermogravimetry and differential scanning calorimetry showed optimal, for drug delivery systems, phase structure: presence of no crystallites and excellent outcome of PES oligomers as plasticizer (significant decrease in glass transition temperature). The obtained results, in the fields of particular components mutual miscibility and compatibility with resveratrol as well as phase transition temperatures, have been confirmed by careful theoretical considerations, utilizing eg. different group contribution methods. Such approach enabled to gain excellent encapsulation efficiency (exceeding 80%) as well as drug loading content of around 4.5%. The results indicate the usefulness of membrane-assisted core-shell encapsulation to prepare colloidally stable, nanoparticulate carrier systems (diameters of approximately 150–250 nm) for resveratrol delivery and sustained release, characterized by very reproducible features and narrowed size distributions (polydyspersity indices <0.1–0.15).