Compartmentalized Nano-MOFs as Co-delivery Systems for Enhanced Antitumor Therapy.

Therapeutic bioactive macromolecules hold great promise in cancer therapy, but challenges such as low encapsulation efficiency and susceptibility to inactivation during the targeted co-delivery hinder their widespread applications. Compartmentalized nano-metal-organic frameworks (nMOFs) can easily load macromolecules in the innermost layer, protect them from the outside environment, and selectively release them in the target location after stimulation, showing great potential in the co-delivery of biomacromolecules. Herein, the rationally designed (GOx + CAT)/ZIF-8@BSATPZ/ZIF-8 (named GCZ@BTZ) nMOFs with compartmentalized structures are employed to deliver cascaded enzymes and the chemotherapeutic drug tirapazamine (TPZ)-conjugated bovine serum albumin (BSATPZ). Benefiting from the compartmentalized structure and protective shell, the GCZ@BTZ system is stable during blood circulation and preferentially accumulates in the tumor. Furthermore, in response to the acidic tumor environment, GCZ@BTZ effectively released the loading enzymes and BSATPZ. Along with the tumor starvation caused by depletion of glucose, cascaded reactions could also contribute to the enhancement of tumor hypoxia, which further activated BSATPZ-based chemotherapy. Notably, in the mouse tumor models, GCZ@BTZ treatment significantly inhibits tumor survival and metastasis. Such a compartmentalized nMOF delivery system presents a promising avenue for the efficient delivery of bioactive macromolecules.