Cooperation of endogenous and exogenous reactive oxygen species induced by zinc peroxide nanoparticles to enhance oxidative stress-based cancer therapy

Reactive oxygen species (ROS)-generating anticancer agents can act through two different mechanisms: (i) elevation of endogenous ROS production in mitochondria, or (ii) formation/delivery of exogenous ROS within cells. However, there is a lack of research on the development of ROS-generating nanosystems that combine endogenous and exogenous ROS to enhance oxidative stress-mediated cancer cell death. Methods: A ROS-generating agent based on polymer-modified zinc peroxide nanoparticles (ZnO₂ NPs) was presented, which simultaneously delivered exogenous H₂O₂ and Zn²⁺ capable of amplifying endogenous ROS production for synergistic cancer therapy. Results: After internalization into tumor cells, ZnO₂ NPs underwent decomposition in response to mild acidic pH, resulting in controlled release of H₂O₂ and Zn²⁺. Intriguingly, Zn²⁺ could increase the production of mitochondrial O₂·^- and H₂O₂ by inhibiting the electron transport chain, and thus exerted anticancer effect in a synergistic manner with the exogenously released H₂O₂ to promote cancer cell killing. Furthermore, ZnO₂ NPs were doped with manganese via cation exchange, making them an activatable magnetic resonance imaging contrast agent. Conclusion: This study establishes a ZnO₂-based theranostic nanoplatform which achieves enhanced oxidative damage to cancer cells by a two-pronged approach of combining endogenous and exogenous ROS.