Ligand‐Engineered Cu ₁₃ Nanoclusters Direct Distinct Programmed Cell Death Pathways for Tumor‐Selective Therapy

ABSTRACT 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 Cu 13 core but differ in peripheral ligands, i.e. Cu 13 ‐OH and Cu 13 ‐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, Cu 13 ‐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, Cu 13 ‐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 Cu 13 ‐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.