Engineering a High-Entropy Driven and Nuclear-Targeted Bioorthogonal Catalyst for Cancer Therapy

Bioorthogonal catalysis mediated by Pd-based catalysts has drawn widespread attention for the treatment of diseases. However, the catalytic performance and durability of current Pd 0 catalysts are unsatisfactory. Herein, a high-entropy driven and nuclear-targeted bioorthogonal system with superior performance and durability has been engineered to enhance the activity and prevent deactivation of Pd for improved antitumor therapy. The high-entropy coordination environment of the high-entropy alloys (HEAs) stabilizes Pd, endowing bioorthogonal catalysts with superior durability. Meanwhile, the multicomponent interactions of HEAs synergistically provide a ligand effect to supply electrons to Pd, thereby improving catalytic performance. Furthermore, we discovered for the first time that HEAs exhibit glutathione peroxidase-like activity by eliminating the antioxidant glutathione to prevent the deactivation of Pd catalysts within intracellular environments. Importantly, the synthesis of drugs at the nucleus by the bioorthogonal system can further amplify the therapeutic effect of Pd 0 -based catalysts in the intracellular environment. Additionally, the photothermal properties of HEAs can enhance catalysis and antitumor effect. This work has the potential to broaden the applications of HEAs and contribute to the design of bioorthogonal catalysts.