Self‐Cascade Nanozyme Reactor as a Cuproptosis Inducer Synergistic Inhibition of Cellular Respiration Boosting Radioimmunotherapy

Abstract Intrinsic or acquired radioresistance remained an important challenge in the successful management of cancer. Herein, a novel “smart” multifunctional copper‐based nanocomposite (RCL@Pd@CuZ) to improve radiotherapy (RT) sensitivity is designed and developed. In this nanoplatform, DSPE‐PEG‐RGD modified on the liposome surface enhanced tumor targeting and permeability; capsaicin inserted into the phospholipid bilayer improved the hypoxic conditions in the tumor microenvironment (TME) by inhibiting mitochondrial respiration; a Cu MOF porous cube encapsulated in liposome generated highly active hydroxyl radicals (OH · ), consumed GSH and promoted cuproptosis by releasing Cu 2+ ; the ultrasmall palladium (Pd) nanozyme within the cubes exhibited peroxidase activity, catalyzing toxic OH · generation and releasing oxygen from hydrogen peroxide; and lastly, Pd, as an element with a relatively high atomic number (Z) enhanced the photoelectric and Compton effects of X‐rays. Therefore, RCL@Pd@CuZ enhance RT sensitivity by ameliorating hypoxia, promoting cuproptosis, depleting GSH, amplifying oxidative stress, and enhancing X‐ray absorption , consequently potently magnifying immunogenic cell death (ICD). In a mouse model , RCL@Pd@CuZ combined with RT yielded >90% inhibition compared with that obtained by RT alone in addition to a greater quantity of DC maturation and CD8 + T cell infiltration. This nanoplatform offered a promising remedial modality to facilitate cuproptosis‐related cancer radioimmunotherapy.