Polydopamine-encapsulated zinc peroxide nanoparticles to target the metabolism-redox circuit against tumor adaptability for mild photothermal therapy†

Regulating the metabolism-redox circuit of cancer cells has emerged as an attractive strategy to improve the therapeutic outcome, while often confronting the glaring issue of resistance due to the multiple adaptive responses of tumor cells. This study presents a simple yet efficient approach to regulate this circuit simultaneously against tumor adaptability by utilizing polydopamine-encapsulated zinc peroxide nanoparticles (ZnO₂@PDA NPs). The nanoparticles could deliver large amounts of Zn²⁺ and H₂O₂ into tumor cells to unfold an intracellular self-amplifying loop for breaking the balance in zinc and redox homeostasis by H₂O₂-mediated endogenous Zn²⁺ release from metallothioneins due to its oxidation by H₂O₂ and Zn²⁺-induced in situ H₂O₂ production by disturbing mitochondrial respiration, ultimately disrupting tumor adaptability to exogenous stimuli. The elevated levels of Zn²⁺ and H₂O₂ also inhibited adenosine triphosphate (ATP) generation from glycolysis and mitochondrial respiration to disrupt energy adaptability. Furthermore, insufficient ATP supply could reduce glutathione and heat shock protein expression, thereby sensitizing oxidative stress and enabling PDA-mediated mild photothermal therapy (PTT). Consequently, this trinity nanoplatform, which integrated dual-starvation therapy, amplified oxidative stress, and mild PTT, demonstrated outstanding therapeutic effects and a facile strategy.