Mesoporous polydopamine composite nanoparticles for multimodal therapy based on disrupting the redox homeostasis within tumor cells

Developing multimodal combination therapy strategies to disrupt the redox homeostasis within tumor cells is currently an important approach in cancer treatment. In this study, we designed and prepared multifunctional composite nanoparticles MPDA-PEG@MnO₂@2-DG (MPPMD NPs) utilizing mesoporous polydopamine nanoparticles (MPDA NPs) as carriers. These carriers were coated with polyethylene glycol (PEG), and manganese dioxide (MnO₂) and loaded with 2-deoxy-d-glucose (2-DG). Studies on mechanism revealed that upon accumulation in tumor cells via in situ injection, MnO₂ can react with overexpressed H₂O₂ to generate Mn²⁺, O₂, and toxic OH. Additionally, MnO₂ undergoes an oxidation-reduction reaction (redox) with glutathione (GSH), consuming GSH and generating Mn²⁺. The resulting Mn²⁺ further participates in Fenton-like reactions with overexpressed H₂O₂ within the tumor. Furthermore, under 808 nm laser, MPPMD NPs facilitate photothermal therapy (PTT), promoting the generation of reactive oxygen species (ROS), inducing oxidative stress, and reducing the adenosine triphosphate (ATP) level. Concurrently, the 2-DG loaded by MPPMD NPs disguised as glucose disrupts the glycolysis process, inhibiting ATP production, and effectively inducing tumor starvation therapy (ST). By leveraging the multifunctionality of MPPMD NPs, this work realized the disruption of redox homeostasis within tumor cells, providing potential strategies for multimodal tumor treatment.