Biomimetic Nano-regulator that Induces Cuproptosis and Lactate-Depletion Mediated ROS Storm for Metalloimmunotherapy of Clear Cell Renal Cell Carcinoma.

Herein, we designed a ccRCC targeting nanodrug to enhance chemodynamic therapy (CDT) as well as activate cuproptosis and tumor immunotherapy via ccRCC cell membrane modifying CuO@Gd 2 O 3 yolk-like particles (CGYL) loaded with lactate oxidase (LOx) (mCGYL-LOx). Benefiting from the homologous targeting effect of Renca cell membranes, the mCGYS-LOx could be effectively internalized by Renca cells, opened the "gate", and then released LOx and copper ions. LOx could catalyze excessive lactate in Renca cells into H 2 O 2 , following that the produced H 2 O 2 was further converted by copper ions to the highly toxic ·OH, contributing to tumor CDT. Meanwhile, the excessive copper ions effectively triggered tumor cuproptosis. These synergistic effects induced the release of damage associated molecular patterns and activated immunogenic cell death, leading to DC maturation and infiltration of immune effector cells. Moreover, LOx-mediated lactate consumption downregulated the expression of PD-L1, crippling tumor immune escape. In addition, the mCGYL-LOx improved T 1 -weighted MRI signal, allowing for accurate diagnosis of ccRCC. This study demonstrated that the mCGYL-LOx had great potential for improving therapy of ccRCC via the synergistic actions of CDT and cuproptosis as well as immunotherapy. This article is protected by copyright. All rights reserved.