MnO2-based bioresponsive nanoplatform synergizing mitochondrial metabolism modulation for amplified phototherapy and chemodynamic therapy of melanoma

Abstract

Phototherapy (PT) against melanoma continues to face significant great challenges with suitable photosensitizers, a hypoxic tumor microenvironment (TME), and aberrant tumor metabolic activities. Herein, we developed a MnO₂-based bioresponsive nanoplatform (PIM NPs) that exerted multi-enzyme activities and synergized mitochondrial metabolism modulation for amplified PT and chemodynamic therapy (CDT) of melanoma. The PIM NPs were constructed by coating the MnO₂ nanozymes shell onto mesoporous polydopamine nanoparticles (mPDA NPs) loaded with photosensitizer (ICG). The PIM NPs consumed H₂O₂ to generate O₂ under acid TME, alleviating hypoxia to promote the photodynamic effect of ICG for producing toxic singlet oxygen (¹O₂). Meanwhile, the PIM NPs depleted glutathione (GSH) and triggered the Fenton-like reaction to destroy the antioxidant defense of the tumor cells. The photothermal property of mPDA NPs further enhanced the multi-enzyme activity and the effect of PT. Finally, the bioresponsive PIM NPs down-regulated glycolysis metabolism and oxidative phosphorylation, which disrupted the energy production and nutrient supply of tumor cells, causing the metabolic disorders of tumor cells. Both in vitro and in vivo results showed significant tumor inhibition, indicating that the PIM NPs achieved “All In One” strategy that combining tumor cell mitochondria metabolic regulation to amplify the effect of PT and CDT for melanoma, providing a promising integrated strategy against metabolic abnormalities of melanoma.