Combinatorial cancer therapy has gained a great attention in the recent years. We have developed multi-reservoir zein-based nanocapsules to accomplish a sequential release pattern characterized by faster resveratrol (RES) release followed by more prolonged exemestane (EXM) delivery. RES is proposed to act firstly by reducing the aromatase enzyme expression thus decreasing the enzyme amount available for binding with EXM which will in turn reduce the required EXM dose and hence side effects. Consequently, EXM slowly released will act by binding to the available aromatase enzyme resulting in inhibition of its activity. This pattern could be obtained via two strategies; the first one includes the formation of non-PEGylated and PEGylated phytosomal RES-phosphatidylcholine complex bilayer as an envelope of the genipin-crosslinked zein-coated oily core containing exemestane and RES. In the second strategy, RES nanocrystals were prepared by anti-solvent precipitation technique and then incorporated in the aqueous phase of the zein nanocapsules to promote fast release of RES. A combined sequential release formula utilizing both phytosomal bilayer and nanocrystal technologies was also developed. Moreover, lactoferrin-targeted zein nanocapsules were also prepared via electrostatic interaction. Drug content, morphological analysis, particle size, zeta potential determination, hemolytic, serum stability and in vitro drug release of the prepared nanoparticles were performed. Finally, scaling up of the optimized formula was tried via spray-drying technology. The optimized formula revealed a superior cytotoxicity where its IC50 decreased by 3 and 4-fold against the MCF-7 cell line and 4T1 Murine cells, respectively, compared to the free drug(s). Cellular uptake of drug-loaded NPs were studied using fluorescein isothiocyanate (FITC) as a model compound to label the NPs. In-vivo pharmacokinetic studies revealed encouraging data, where zein NCs exhibited a longer circulation time with markedly delayed blood clearance of the loaded drugs. The anti-tumor superiority of zein NPs over the free drug(s) was manifested as a marked reduction in the percentage change of tumor volume. Mechanistically, the anti-tumor properties of the fabricated formulae were correlated to their ability to inhibit aromatase enzyme, activate apoptotic enzyme, caspase 3, prohibit cyclin D1 and suppress the tumor angiogenic marker, VEGF. Histopathological studies were done and different tumor growth biomarkers were determined. These results confirmed the beneficial synergistic anti-tumor effects obtained from combining EXM/RES in treatment of breast cancer.