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Lupeol (LP) and Mangiferin (MG) have beneficial effects on health. However, their pharmacokinetic properties can affect their bioavailability when administered orally. Therefore, their incorporation as a vehicle in a hybrid matrix of ZnO and PLGA could contribute to improving bioavailability., Methods: This study aimed to develop this matrix and evaluate the optical and bioactive properties obtained by the solvent emulsion and evaporation methods. These were subjected to processes to evaluate their bioactivity in relation with topoisomerase., Results: Functionalized treatment number 15 (T F 15) showed the best results in studies of controlled release and encapsulation efficiency of lupeol (LP) and mangiferin (MG) (60.01 ± 1.24% and 57.71 ± 1.94%). The best treatment showed behavior as a topoisomerase II inhibitor (18.60 ± 1.55). The nanoparticles developed in this study did not show a cytotoxic effect on BEAS-2B, while HepG2, showed a decrease in viability (IC50 1549.96 ± 174.62 μg/mL). However, although the hemolytic activity is not shown after 1 h of exposure, morphological alterations caused by T F 15 are observed at concentrations of 2500 and 1250 μg/mL., Conclusion: The TF15 treatment shown maintaining antitopoisomerasa activity does and does not cytotoxixity for healthy cells and slows down the growth of cancer cells., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)