An Activatable Caged Palladium Nanocomposite for Targeted Cancer Therapy

Abstract Pd‐based intracellular catalysis has attracted increasing interest in modulating biological processes or disease treatment. The unsatisfactory catalytic efficiency arising from limited active sites and poor water solubility of palladium nanoparticles (Pd NPs) and their “always on” catalytic activities pose, however, significant limitations. Herein, we develop a high‐performance nanocomposite based on ultrafine Pd NPs confined within molecular cages, and incorporated with glucose oxidase (GOx) and AS1411 aptamer‐modified hyaluronic acid (HA). The cage‐confined strategy enables facile synthesis of ultrafine Pd NPs with more accessible active sites, significantly improving the catalytic activities of Pd NPs for enhanced bioorthogonal catalysis. Importantly, the nanocomposite exhibits targeting ability and activatable activity in response to both the acidic pH and hyaluronidase overexpressed in the tumor environment, enabling selective drug synthesis. Besides, it features CAT‐, OXD‐, and GPx‐like activities, promoting reactive oxygen species (ROS) generation and intracellular GSH depletion to elevate oxidative stress for enhanced therapy. The cage‐confined configuration makes it possible to establish metal‐based intracellular catalytic systems with high performance, enabling the synthesis of desired molecules for effective disease theranostics.