Dendrimer-Cu(II) Complexes Mediate Enzyme Delivery for Lactate Depletion-Enhanced Combinational Treatment of Leukemia and Glioma

Cancer cells engage in active aerobic glycolysis to meet their bioenergetic synthesis needs, which is known as the Warburg effect. Such a process leads to lactate accumulation in the tumor microenvironment (TME), further promoting cancer progression and inducing immunosuppression. Herein, functionalized dendrimer-Cu(II) complexes (for short, D-Cu(II)) as a nanocarrier, which enables a Fenton-like reaction is developed to generate a large amount of hydroxyl radicals and shows a T₁-weighted magnetic resonance (MR) imaging performance. Importantly, the D-Cu(II) allows efficient delivery of lactate oxidase (LOx) to cancer cells, directly downregulating the lactate levels. When combining with an immune activator of leukadherin-1, the developed D-Cu(II)/LOx complexes alleviate the symptoms of mouse leukemia. With a further coating of macrophage membranes, the generated D-Cu(II)/LOx@M allows for effective blood-brain barrier crossing to treat an orthotopic murine glioma model under the guidance of Cu(II)-facilitated MR imaging. By integrating the LOx-mediated lactate depletion with Cu(II)-mediated chemodynamic therapy, the developed dendrimer nanomedicines improve the overall survival and antitumor immune responses of mice, and help to remodel the immunosuppressive TME in both cancer models, greatly sensitizing the treatment efficacy of immune activator. Such dendrimer technology may further be used for theranostics of other cancer types through lactate depletion-enhanced combinational therapy.