Endogenous Nitric Oxide Releases In Situ for RNS/ROS Synergistic Cancer Therapy

Abstract Gas therapy, represented by nitric oxide (NO), has shown a powerful anti‐tumor effect. However, current NO therapy relies on NO precursors, which are often released prematurely during in vivo delivery, resulting in poor targeting and obvious toxic side effects. Herein, a core/shell‐structured nanocatalyst is designed and prepared to catalyze the generation of NO in tumor without introduction of NO donor. In this system, C‐Z@CM is prepared by coating the octahedron of Cu‐MOF with a nano‐ZnO, and camouflaging homologous tumor cell membrane. After the nanomedicine is taken up by tumor cells, ZnO reacts in situ with endogenous S‐nitrosoglutathione (GSNO), which is highly expressed in tumors, to continuously and stably generate NO. In addition, the dispersed copper ions in C‐Z@CM acts as the catalytic active centers of the Fenton‐like reaction, which catalyzes H₂O₂ to generate a large number of hydroxyl radicals (^•OH). Importantly, the cascade of NO and reactive oxygen species (ROS) leads to the massive production of more lethal reactive nitrogen species (RNS), further enhancing the therapeutic effect. Catalytic production of high concentrations of NO in situ in the tumor, combined with the cascade generation of ROS and RNS, accompanied by glutathione (GSH) depletion, achieving effective tumor suppression.