Ligand-Engineered Cu₁₃ Nanoclusters Direct Distinct Programmed Cell Death Pathways for Tumor-Selective Therapy

Programmed cell death (PCD) pathways such as apoptosis and pyroptosis play a pivotal role in cancer therapy, yet achieving precise and selective activation of these pathways using nanomaterials remains a major challenge. Here, we report the synthesis of two quasi-structurally isomeric 13-nuclear copper nanoclusters that share an identical Cu₁₃ core but differ in peripheral ligands, i.e. Cu₁₃-OH and Cu₁₃-F. These ligand-engineered nanoclusters elicit different cellular localization and reactive oxygen species (ROS) generation profiles, and thereby selectively activate distinct PCD mechanisms for efficient and low-toxicity tumor therapy. Specifically, Cu₁₃-OH anchors onto cell membranes and forms nano-spike protrusions that disrupt cytoskeletal organization and suppress PI3K-AKT signalling, leading to caspase-dependent apoptosis with a concentration-threshold response. In contrast, Cu₁₃-F shows enhanced cellular uptake/internalization and stronger ROS-generation capability, which may be associated with fluorination-modulated copper redox behavior, thereby activating Caspase-4/Gsdmd-mediated pyroptosis. Both in vitro and in vivo studies conclude potent tumor-selective inhibition, particularly that Cu₁₃-F exhibits exceptional efficacy at low-doses due to its enhanced membrane permeation and robust ROS generation. These findings confirm ligand engineering as a versatile strategy for precise spatial modulation of PCD pathways, offering a new paradigm for feasible design of tumor-selective nanomedicines through subtle atomic-level modifications.