Ultrathin 2D Pd/Cu Single-Atom MOF Nanozyme to Synergistically Overcome Chemoresistance for Multienzyme Catalytic Cancer Therapy

Single-atom nanozymes (SAzymes) have obtained increasing interest to mimic natural enzymes for efficient cancer therapy, while challenged by chemoresistance from cellular redox homeostasis and the interface of reductive species in tumor microenvironment (TME). Herein, a dual single-atomic ultrathin 2D metal organic framework (MOF) nanosheet of multienzyme (Pd/Cu SAzyme@Dzy) is prepared to synergistically overcome chemoresistance for multienzyme enhanced cancer catalytic therapy. The Pd SAzyme exhibits peroxidase (POD)-like catalytic activity for overcoming chemoresistance via disturbing cellular redox balance. This is further enhanced by cascade generation of more & BULL;OH via Cu+-catalyzed POD-like reactions, initiated by in situ-reduction of Cu2+ into Cu+ upon GSH depletion. This process can also avoid the consumption of & BULL;OH by endogenous reductive GSH in TME, ensuring the adequate amount of & BULL;OH for highly efficient therapy. Besides, the DNAzyme is 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 multienzyme-based cancer therapy is examined and the enhancement by the cascade tumor antichemoresistance is revealed. To overcome chemoresistance of single-atom nanozyme from cellular redox homeostasis and interface of reductive species, a dual single-atomic ultrathin 2D MOF nanosheet of multienzyme is prepared. Chemoresistance is overcome upon disrupting cell redox homeostasis by excessive & BULL;OH from cascade catalytic reactions and GSH depletion. DNAzyem also exhibits efficient gene therapy for obtaining synergistical multienzyme catalytic cancer therapy.image