Single-Site Nanozymes with a Highly Conjugated Coordination Structure for Antitumor Immunotherapy via Cuproptosis and Cascade-Enhanced T Lymphocyte Activity

Abstract

The extracellular matrix (ECM) in the tumor microenvironment (TME) and upregulated immune checkpoints (ICs) on antitumor immune cells impede the infiltration and killing effect of T cells, creating an immunosuppressive TME. Herein, a cholesterol oxidase (CHO) and lysyl oxidase inhibitor 2,3,6,7,10,11,14,15-octaol single-site nanozyme (Cu-DBCO/CL) was developed. The conjugated organic ligand and well-distributed Cu-O 4 sites endow Cu-DBCO with unique redox capabilities, enabling it to catalyze O 2 and H 2 O 2 to •O 2− and •OH. This surge of reactive oxygen species (ROS) leads to impaired mitochondrial function and insufficient ATP supply, impacting the function of copper-transporting ATPase-1 and causing dihydrolipoamide Sacetyltransferase oligomerization-mediated cuproptosis. Moreover, multiple ROS storms and glutathione peroxidase 4 depletion also induce lipid peroxidation and trigger ferroptosis. Simultaneously, the ROS-triggered release of LOX-IN-3 reshapes the ECM by inhibiting lysyl oxidase activity and further enhances the infiltration of cytotoxic T lymphocytes (CD8 + T cells). CHO-triggered cholesterol depletion not only increases •OH generation but also downregulates the expression of ICs such as PD-1 and TIM-3, restoring the antitumor activity of tumor-infiltrating CD8 + T cells. Therefore, Cu-DBCO/CL exhibits efficient properties in activating a potent antitumor immune response by cascade-enhanced CD8 + T cell viability. More importantly, ECM remodeling and cholesterol depletion could suppress the metastasis and proliferation of the tumor cells. In short, this immune nanoremodeler can greatly enhance the infiltration and antitumor activity of T cells by enhancing tumor immunogenicity, remodeling ECM, and downregulating ICs, thus achieving effective inhibition of tumor growth and metastasis.

Metal–Organic Framework-Based Nanovaccine for Relieving Immunosuppressive Tumors via Hindering Efferocytosis of Macrophages and Promoting Pyroptosis and Cuproptosis of Cancer Cells

“…Cu-THBQ alone cannot generate • OH in aqueous solution, but it can effectively generate • O 2 – in the presence of oxygen in aqueous solution, as demonstrated by the enhanced fluorescence intensity of dihydrorhodamine 123 (a • O 2 – probe) (Figure e). The reason for this phenomenon is that the THBQ ligand and the central copper ion within Cu-THBQ possess a range of redox intermediates, enabling semiquinone radicals to effectively catalyze the conversion of O 2 to • O 2 – (Figure f). , The CL intensity of AMPPD, a substrate that can correspond to AP, remained almost unchanged within 40 min (Figure g), and the position of the emission peak also coincided with the absorption peak of Cu-THBQ (Figure h). Next, the ability of Cu-THBQ/A to generate • O 2 – via CL-activated type I photodynamic reactions was further evaluated in the presence of AP (Figure i).…”

Modulating Electron Transfer between Pt and MOF Support through Pd Doping Promotes Nanozyme Catalytic Efficiency

“…Specifically, the Pt 4 Pd 1 @ZIF-8 nanozyme exhibited the best catalytic activity with a moderate electron transfer number. The reaction energy barrier of the rate-limiting step was closely related to the Gibbs free energy of crucial intermediates in the catalytic reaction. − Mechanism studies on the adsorption energy of crucial intermediates indicated that with the introduction of Pd, the adsorption affinity of Pt toward crucial intermediates exhibited a progressive augmentation, ultimately reaching an optimal state at Pt 4 Pd 1 @ZIF-8. Further increases in Pd content hindered the desorption of crucial intermediates.…”

Carrier‐Free Self‐Assembly Nano‐Sonosensitizers for Sonodynamic‐Amplified Cuproptosis‐Ferroptosis in Glioblastoma Therapy

“…[ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ] Cuproptosis is a new programmed cell death induced by Cu‐dependent mitochondrial dysfunction, which is distinct from apoptosis, necroptosis, ferroptosis, and pyroptosis. [ 15 , 16 , 17 , 18 , 19 , 20 ] Cuproptosis primarily relies on the accumulation of intracellular Cu into mitochondria, regulating tricarboxylic acid cycle (TCA) related metabolism. As regards the mechanism of action, ferredoxin‐1 (FDX1) and lipoyl synthase (LIAS) regulate dihydrolipoamide S‐acetyltransferase (DLAT) to undergo lipoylation.…”