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.