A Responsive Nanorobot Modulates Intracellular Zinc Homeostasis to Amplify Mitochondria‐Targeted Phototherapy

Abstract Zinc has been proven to interweave with many critical cell death pathways, and not only exhibits potent anticancer activity solely, but sensitizes cancer cells to anticancer treatment, making zinc supplementation ideal for boosting odds against malignancy. Herein, a smart nanorobot (termed as Zinger) is developed, composed of iRGD‐functionalized liposome encapsulating black phosphorus nanosheet (BPNs) doped zeolite imidazole framework‐8 (BPN@ZIF‐8), for advancing zinc‐promoted photodynamic therapy (PDT). Zinger exhibits photo‐triggered sequential mitochondria‐targeting ability, and can induce zinc overload‐mediated mitochondrial stress, which consequently sensitized tumor to PDT through synergistically modulating reactive oxygen species (ROS) production and p53 pathway. It is identified that Zinger selectively triggered intracellular zinc overload and photodynamic effect in cancer cells, which together enhanced PDT treatment outcomes. Importantly, Zinger shows high efficacy in overcoming various treatment barriers, allowing for effectively killing cancer cells in the complex circumstances. Particularly, Zinger exhibits good tumor accumulation, penetration, and even cell uptake, and can respond to light stimulation to eliminate tumors while avoiding normal tissues, thereby prolonging survival of tumor‐bearing mice. Therefore, the study provides a novel insight in the development of novel zinc‐associated therapy for advancing cancer treatment approaches.