Near-Infrared Light-Accelerated Bioorthogonal Drug Uncaging and Photothermal Ablation by Anisotropic Pd@Au Plasmonic Nanorods

Selective activation of chemotherapeutics at the tumor site via bioorthogonal catalysis is a promising strategy to reduce collateral damage to healthy tissues and organs. Despite significant advances in this field, targeted drug activation by transition-metal catalysts is still limited by insufficient spatiotemporal control over the metal-mediated uncaging process. Herein, we report the development of anisotropic Pd@Au plasmonic nanorods with the capacity to accelerate dealkylation reactions under near-infrared (NIR) irradiation, thereby enabling precise control over when and where these catalytic devices are switched on. We also show that the stability and in cellulo chemical properties of Pd@Au nanorods are enhanced by Au–S functionalization with PEGylated phospholipids and report the development of a novel masking group for prodyes and prodrugs: the POxOC group, designed to improve physicochemical properties and the rate of the Pd-triggered dye/drug release process. NIR-photoactivation of lipo-Pd@Au nanorods is able to catalyze the uncaging of inactive drug precursors and release heat to the environment, killing cancer cells in culture and xenografted in zebrafish. This work provides a novel targeted strategy for photothermal chemotherapy by NIR-laser focalization.