Biomimetic Nano‐Regulator that Induces Cuproptosis and Lactate‐Depletion Mediated ROS Storm for Metalloimmunotherapy of Clear Cell Renal Cell Carcinoma

Abstract Herein, a ccRCC targeting nanodrug is designed 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 can be effectively internalized by Renca cells, open the “gate”, and then release LOx and copper (Cu) ions. LOx can catalyze excessive lactate in Renca cells into H 2 O 2 , following that the produced H 2 O 2 is further converted by Cu ions to the highly toxic ·OH, contributing to tumor CDT. Meanwhile, the excessive Cu ions effectively trigger tumor cuproptosis. These synergistic effects induce the release of damage associated molecular patterns (DAMPs) and activate immunogenic cell death (ICD), leading to DC maturation and infiltration of immune effector cells. Moreover, LOx‐mediated lactate consumption downregulates the expression of PD‐L1, crippling tumor immune escape. In addition, the mCGYL‐LOx improves T 1 ‐weighted MRI signal, allowing for accurate diagnosis of ccRCC. This study demonstrates that the mCGYL‐LOx has great potential for improving therapy of ccRCC via the synergistic actions of CDT and cuproptosis as well as immunotherapy.