Mitochondria-Targeted Polyoxometalate Nanostructures with Thermal Sensitization Properties for Enhanced Photothermal Therapy

Photothermal therapy (PTT) is hampered by cellular thermal resistance caused by the overexpression of heat-resistant proteins and related encoded genes. Here, we propose a method to reduce thermal resistance through an energy depletion-mediated heat-sensitization strategy, which in turn enhances tumor-specific PTT. We synthesized polyoxometalates (POM)/calcium phosphate (CaP) composite nanospheres (NSs) modified with triphenylphosphine (TPP) to load the glycolysis inhibitor 2-deoxy- d -glucose (2DG) (TPC/2DG NSs). TPC/2DG NSs not only have excellent photothermal effects but also cause oxidative damage to the mitochondria. Responsive degradation and photothermal effects enable a spatiotemporally controlled release. The released 2DG reduces adenosine triphosphate (ATP) levels by inhibiting tumor anaerobic glycolysis synergistically with mitochondrial dysfunction, impedes the generation of heat shock proteins (HSPs), and eventually enhances the heat sensitivity of tumors to PTT, thereby improving therapeutic efficiency. The mitochondria-targeted POM nanostructure with thermal sensitization properties offers a prospective strategy for the ATP energy depletion/PTT synergistic treatment of tumors.