“Block and attack” strategy for tumor therapy through ZnO ₂ /siRNA/NIR‐mediating Zn ²⁺ ‐overload and amplified oxidative stress

Abstract Intracellular zinc ion (Zn 2+ ) accumulation disrupts the Zn 2+ 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 Zn 2+ via gene silencing and “attacking” tumor cells via target delivery of ZnO 2 . After cellular internalization, ZnO 2 was degraded to Zn 2+ and hydrogen peroxide (H 2 O 2 ), and the gene expression of zinc transporter 1 (ZnT1) was silenced by targeting of released siRNA, which together caused intracellular Zn 2+ ‐overload. Disorder of Zn 2+ further interfered with intracellular Ca 2+ 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.