Abstract

Nanozyme-catalyzed reactive oxygen species (ROS) generation has emerged as a promising strategy for advanced ROS-based therapeutics. However, achieving efficient ROS production with favorable catalytic kinetics in a confined microenvironment remains challenging. Herein, a cancer-targeting heterogeneous Janus nanozyme (JN, Cu 2– x Se–Au-TLS11a) was rationally fabricated via a facile modular synthesis and assembly. Upon near-infrared II (NIR-II) light irradiation, the well-designed JN realized multimodal synergistic anticancer effects via three coordinated mechanisms: (i) efficient photothermal conversion with a high efficiency of 61.9% for photothermal therapy (PTT); (ii) NIR-II-triggered hot-electron transfer from the Au domain to Cu 2– x Se promoted the generation of Cu + , which accelerated Fenton-like reactions to produce hydroxyl radicals (•OH); and (iii) NIR-II photoexcitation induced the formation of electron–hole (e – -h + ) pairs on the Janus nanostructure, enabling additional photocatalytic •OH generation. Under NIR-II light activation, the JNs, integrating photothermal, photoenhanced chemodynamic, and photocatalytic effects, demonstrated highly specific and potent in vitro anticancer efficacy, achieving an IC 50 value of approximately 12.5 μg mL –1 against HepG2 cells and reducing cell viability to 13.8%, thereby providing an innovative paradigm for designing spatiotemporally controlled, ROS-amplifying nanoplatforms toward precision cancer therapy.