AuAgPt Trimetallic Alloy Nanoframes as Metabolic Regulators for Highly Efficient Low-Temperature Photothermal Therapy.

Low-temperature photothermal therapy (PTT) offers a promising alternative to traditional high-temperature PTT by minimizing damage to healthy tissues at mild temperatures (<45 °C), yet its efficacy is significantly challenged by the upregulation of heat shock proteins (HSPs) and low tumor ablation efficiency. Here AuAgPt trimetallic alloy nanoframes (AuAgPt NFs) are introduced as metabolic regulators, which can enter tumor cells to generate stable low-temperature photothermal effect (ca. 42 °C) under near-infrared irradiation, possess high catalytic activity to consume H2O2 and concentrate reactive oxygen species (ROS), and efficiently adsorb and remove glutathione (GSH). Furthermore, the intracellular local heating can perturb the levels of 14 metabolites including amino acids, adenine, uric acid and pyridoxine, leading to oxidative stress. All of these alterations caused by AuAgPt NFs can downregulate GPX4 and HSPs, and increase the Bax/Bcl-2 ratio, ultimately inducing ferroptosis and apoptosis to kill tumor cells. In vivo experiments demonstrate effective tumor ablation while maintaining high biosafety profiles. AuAgPt NFs featuring catalytic, adsorptive, and photothermal properties are constructed to synergistically regulate intracellular metabolites for inducing programmed cell death, providing a highly promising low-temperature PTT strategy.