Dual-upregulation of p53 for self-sensitized cuproptosis via microwave dynamic and NO gas therapy.

Cuproptosis-a novel cell death mechanism-is an innovative strategy for tumor therapy. However, the insufficient efficacy of cuproptosis, primarily owing to the low sensitivity of tumor cells to Cu ions, remains a major challenge. In this study, we design TiCuMOF@PEG@l-Arg@TPP (TCPAT) nanoparticles to facilitate self-sensitized cuproptosis for anti-tumor therapy through the dual upregulation of p53. TiMOF serves as a microwave sensitizer by generating reactive oxygen species (ROS). Notably, the uniformly distributed Cu ions within the MOF serve as co-catalysts to provide reactive sites that enhance ROS generation. Additionally, the ROS generated are utilized to oxidize l-arginine, thus resulting in the release of nitric oxide (NO), which has a long half-life and diffusion distance, thereby enabling it to penetrate deep into the tumor regions that are typically inaccessible to ROS. Furthermore, TCPAT not only induces cuproptosis but also leverages the efficiently generated ROS and cascade-released NO for the dual upregulation of p53. This upregulation subsequently inhibits glycolysis, increases cellular sensitivity to Cu ions, and facilitates self-sensitized cuproptosis. Consequently, the self-sensitized cuproptosis strategy, dependent on the efficient generation of ROS, presents a promising avenue for tumor therapy based on cuproptosis mechanisms.