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 BiO2‐x wrapped with CaCO3 (named BiO2‐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 BiO2‐x defects, which enables highly efficient photocatalysis of CO2‐to‐CO. Meanwhile, such BiO2‐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.

Biodegradable Bismuth Nanostructures as a Ferroptosis Inducer for Phototherapy of Breast Cancer

“…Bismuth (Bi) is a green heavy metal that usually shows low toxicity. Many Bi-based drugs have been developed to treat tumors and other diseases. − Bi-based semiconductor nanomaterials have remarkable potential in PDT because of their low price, easy synthesis, controllable preparation form, and unique electronic structure. , Therefore, the design of the Bi-based semiconductor nanotherapy platform can achieve ROS release. Furthermore, Bi ions can also coordinate with GSH and achieve ferroptosis through the depletion of GSH in the tumor microenvironment (TME) through the photogenerated hole in the valence band (VB). , …”