Vacancy‐Rich Bismuth‐Based Nanosheets for Mitochondrial Destruction via CO Poisoning, Ca²⁺ Dyshomeostasis, and Oxidative Damage

Abstract Mitochondria are core regulators of tumor cell homeostasis, and their damage has become an arresting therapeutic modality against cancer. Despite the development of many mitochondrial‐targeted pharmaceutical agents, the exploration of more powerful and multifunctional medications is still underway. Herein, oxygen vacancy‐rich BiO_2‐x wrapped with CaCO₃ (named BiO_2‐x@CaCO₃/PEG, BCP) is developed for full‐fledged attack on mitochondrial function. After endocytosis of BCP by tumor cells, the CaCO₃ shell can be decomposed in the acidic lysosomal compartment, leading to immediate Ca²⁺ release and CO₂ production in the cytoplasm. Near‐infrared irradiation enhances the adsorption of CO₂ onto BiO_2‐x defects, which enables highly efficient photocatalysis of CO₂‐to‐CO. Meanwhile, such BiO_2‐x nanosheets possess catalase‐, peroxidase‐ and oxidase‐like catalytic activities under acidic pH conditions, allowing hypoxia relief and the accumulation of diverse reactive oxygen species (ROS) in the tumor microenvironment. Ca²⁺ overload‐induced ion dyshomeostasis, CO‐mediated respiratory chain poisoning, ROS‐triggered oxidative stress aggravation, and cytosolic hyperoxia can cause severe mitochondrial disorders, which further lead to type I cell death in carcinoma. Not only does BCP cause irreversible apoptosis, but immunogenic cell death is simultaneously triggered to activate antitumor immunity for metastasis inhibition. Collectively, this platform promises high benefits in malignant tumor therapy and may expand the medical applications of bismuth‐based nanoagents.