Mitochondria-targeted CORM-401 nanoparticles inhibit A549 cells by triggering cuproptosis

OBJECTIVE: In this study, mitochondrial-targeted nanoparticles containing CORM-401 were designed by using TPP and HA (named as CORM-TPP@HA). The effects of these nanoparticles on cuproptosis in A549 cells were observed to confirm their function. METHODS: First, CORM-TPP micelles were formed by using CORM-401 and TPP-SH. Then, the micelles were encapsulated with HA to form nanoparticles (CORM-TPP@HA). The morphology, size distribution, stability, and release of CO from nanoparticles were analyzed to confirm their characterization. Meanwhile, the cellular uptake of nanoparticles was observed using a confocal microscope. The effects of the nanoparticles on cell viability, mitochondrial ROS, intracellular copper, and cuproptosis-related proteins in A549 cells were measured. Additionally, the impacts of nanoparticles on tumor growth and cuproptosis-related factors in tumor tissue were measured in vivo. RESULTS: The designed nanoparticles maintained stable formation, effectively preventing premature CO release from CORM-401. Furthermore, the nanoparticles were able to be taken up by A549 cells. Moreover, treatment with the designed nanoparticles induced cuproptosis by increasing mitochondrial ROS, intracellular copper, and cuproptosis-related proteins in A549 cells. In line with the in vitro results, treatment with nanoparticles suppressed tumor growth and elevated the cuproptosis-related proteins in tumor tissues. CONCLUSION: The synthesized CORM-TPP@HA nanoparticles suppressed A549 cells via regulating mitochondrial cuproptosis, providing a signaling mechanism of CO in NSCLC treatment.