Ultrathin 2d Pd/Cu Single-Atom Mof Nanozyme to Synergistically Overcome Chemoresistance for Multi-Enzyme Catalytic Cancer Therapy.

Single-atom nanozymes (SAzymes) have obtained increasing interests to mimic natural enzymes for efficient cancer therapy, while challenged by chemoresistance from cellular redox homeostasis and interface of reductive species in tumor microenvironment (TME). Herein, a dual single-atomic ultrathin 2D MOF nanosheet of multi-enzyme (Pd/Cu SAzyme@Dzy) was prepared to synergistically overcome chemoresistance for multi-enzyme enhanced cancer catalytic therapy. The Pd SAzyme exhibited the peroxidase (POD)-like catalytic activity for overcoming chemoresistance via disturbing cellular redox balance. This was further enhanced by cascade generation of more •OH via Cu + -catalyzed POD-like reactions, initiated by in situ-reduction of Cu 2+ into Cu + upon GSH depletion. This process can also avoid the consuming of •OH by endogenous reductive GSH in TME, ensuring the adequate amount of •OH for highly efficient therapy. Besides, the DNAzyme was also delivered for gene therapy of silencing cancer-cell-targeting VEGFR2 protein to further enhance the therapy. Based on both experiments and theoretical calculations, the synergetic multi-enzyme-based cancer therapy has been examined and the enhancement by the cascade tumor anti-chemoresistance was revealed. This article is protected by copyright. All rights reserved.