BACKGROUND: Many cancer cell lines, such as Hepa 1-6 (liver), A549 (lung), Hela (cervical), and MCF7 (breast), do not overexpress tyrosinase, an enzyme needed to activate the prodrug quercetin into its active form, o-quinone. In addition, these cancers do not rely on extracellular tyrosine for growth, as they can produce small amounts intracellularly. METHODS: We investigate two therapeutic strategies using nanocapsules containing polyhemoglobin-tyrosinase (PolyHb-Tyr-nano) for action on (1) the intracellular activation of quercetin to o-quinone and (2) the depletion of intracellular tyrosine. We applied these strategies to the four cell lines listed above. RESULTS: (1) PolyHb-Tyr-nano activates quercetin intracellularly, increasing o-quinone levels and reducing cancer cell viability. (2) PolyHb-Tyr-nano alone suppresses tumor growth by lowering intracellular tyrosine. Furthermore, PolyHb-Tyr-nano shows selective cytotoxicity, with an LD(50) of 0.7808 mg/mL in Hepa 1-6, compared with an extrapolated LD(50) of 84,181 mg/mL in the normal liver cells. In contrast, quercetin activation results in an LD(50) of 2.73 mg/mL in Hepa 1-6 and 74.18 mg/mL in normal hepatocytes. CONCLUSIONS: PolyHb-Tyr-nano offers dual therapeutic functions: (1) quercetin prodrug activation and (2) intracellular tyrosine depletion.