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

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.

Gold Nanodots-Anchored Cobalt Ferrite Nanoflowers as Versatile Tumor Microenvironment Modulators for Reinforced Redox Dyshomeostasis.

Given that tumor microenvironment (TME) exerts adverse impact on the therapeutic response and clinical outcome, robust TME modulators may significantly improve the curative effect and increase survival benefits of cancer patients. Here, Au nanodots-anchored CoFe2O4 nanoflowers with PEGylation (CFAP) are developed to respond to TME cues, aiming to exacerbate redox dyshomeostasis for efficacious antineoplastic therapy under ultrasound (US) irradiation. After uptake by tumor cells, CFAP with glucose oxidase (GOx)-like activity can facilitate glucose depletion and promote the production of H2O2. Multivalent elements of Co(II)/Co(III) and Fe(II)/Fe(III) in CFAP display strong Fenton-like activity for·OH production from H2O2. On the other hand, energy band structure CFAP is superior for US-actuated 1O2 generation, relying on the enhanced separation and retarded recombination of e-/h+ pairs. In addition, catalase-mimic CFAP can react with cytosolic H2O2 to generate molecular oxygen, which may increase the product yields from O2-consuming reactions, such as glucose oxidation and sonosensitization processes. Besides the massive production of reactive oxygen species, CFAP is also capable of exhausting glutathione to devastate intracellular redox balance. Severe immunogenic cell death and effective inhibition of solid tumor by CFAP demonstrates the clinical potency of such heterogeneous structure and may inspire more relevant designs for disease therapy.