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

Area of Science:

• Nanomedicine
• Cancer Therapy
• Cell Death Pathways

Background:

• Programmed cell death (PCD) pathways like apoptosis and pyroptosis are crucial in cancer therapy.
• Precise and selective activation of these PCD pathways using nanomaterials is a significant challenge.

Purpose of the Study:

• To synthesize and characterize quasi-structurally isomeric 13-nuclear copper nanoclusters (Cu13-OH and Cu13-F) with distinct peripheral ligands.
• To investigate how ligand engineering influences nanocluster localization, reactive oxygen species (ROS) generation, and subsequent activation of specific PCD mechanisms.
• To evaluate the potential of these ligand-engineered nanoclusters for selective and low-toxicity tumor therapy.

Main Methods:

• Synthesis of two isomeric 13-nuclear copper nanoclusters (Cu13-OH and Cu13-F) differing in peripheral ligands.
• Assessment of cellular localization, ROS generation profiles, and PCD pathway activation (apoptosis and pyroptosis) for each nanocluster.
• In vitro and in vivo studies to evaluate tumor-selective inhibition and therapeutic efficacy.

Main Results:

• Cu13-OH nanoclusters anchor to cell membranes, disrupting cytoskeletal organization and suppressing PI3K-AKT signaling to induce caspase-dependent apoptosis.
• Cu13-F nanoclusters exhibit enhanced cellular uptake and ROS generation, activating Caspase-4/Gsdmd-mediated pyroptosis.
• Both nanoclusters demonstrated potent tumor-selective inhibition in vitro and in vivo, with Cu13-F showing exceptional low-dose efficacy.

Conclusions:

• Ligand engineering of copper nanoclusters provides a versatile strategy for precise spatial modulation of PCD pathways.
• Subtle atomic-level modifications can lead to distinct cellular behaviors and therapeutic outcomes.
• This approach offers a new paradigm for designing feasible tumor-selective nanomedicines.