“Block and attack” strategy for tumor therapy through ZnO₂/siRNA/NIR-mediating Zn²⁺-overload and amplified oxidative stress

Intracellular zinc ion (Zn²⁺) accumulation disrupts the Zn²⁺ homeostasis, providing an ion-overloading anticancer strategy with great potential. The self-adaptation of tumor cells to ion concentration, however, puts forward higher requirements for the design of ion-overloading strategy. Herein, “block and attack” antitumor strategy was applied through a composite nanomaterials (UHSsPZH NPs). The strategy demonstrated powerful ion interference ability through both “blocking” the efflux of excess Zn²⁺ via gene silencing and “attacking” tumor cells via target delivery of ZnO₂. After cellular internalization, ZnO₂ was degraded to Zn²⁺ and hydrogen peroxide (H₂O₂), and the gene expression of zinc transporter 1 (ZnT1) was silenced by targeting of released siRNA, which together caused intracellular Zn²⁺-overload. Disorder of Zn²⁺ further interfered with intracellular Ca²⁺ homeostasis, inhibited the electron transport chain and promoted the production of endogenous reactive oxygen species (ROS), which assisted the “attack” to tumor cells together with the exogenous ROS generated by UHSsPZH NPs under 980 nm laser irradiation. In summary, this work supplies a “block and attack” strategy for the application of ion homeostasis interference in tumor therapy.