A Multichannel Metabolic Pathway Interference Strategy for Complete Energy Depletion-Mediated Cancer Therapy

Hydrogen sulfide (H2S) is being progressively integrated as an emerging inhibitor of the electron transport chain in energy interference-based tumor therapy. However, metabolic reprogramming in cancer cells causes both oxidative phosphorylation (OXPHOS) and glycolysis to occur simultaneously, which contributes to the ineffective therapeutic effect of blocking a single pathway. To achieve complete suppression of energy production, an inorganic H2S donor ZnS@ZIF-8@CaP nanoparticle (ZSZC NP) carrying Ca and Zn is constructed for achieving simultaneous interference of OXPHOS and glycolysis. The core-shell ZSZC nanoparticles can break down in the tumor microenvironment. This leads to a sustained H2S release and calcium overload to disrupt the normal functioning of mitochondria by inhibiting the expression of cytochrome c and causing damage to mitochondrial membrane potential. Meanwhile, the presence of Zn2+ hinders the typical process of glycolysis by impeding the functioning of lactate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase. The synchronous interference of OXPHOS and glycolysis hampers the energy supply to cancer cells. Additionally, H2S and calcium overload can expedite tumor necrosis in vivo by inducing cellular acidification and calcification. Therefore, this energy-blocking strategy will completely deplete the energy reserves of cancer cells and provide new insights for exploring bioenergetic inhibition as a treatment approach. An inorganic H2S donor ZnS@ZIF-8@CaP nanoparticle (ZSZC NP) is synthesized and exhibits degradation behavior in tumor microenvironment. ZSZC NPs can achieve synchronous interference of oxidative phosphorylation and glycolysis to deplete the energy supply of cancer cells. Meanwhile, calcification and acidosis caused by calcium overload and H2S therapy can accelerate cell death. image