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Chemodynamic therapy (CDT), enabling selective therapeutic effects and low side effect, attracts increasing attention in recent years. However, limited intracellular content of H 2 O 2 and acid at the tumor site restrains the lasting Fenton reaction and thus the anticancer efficacy of CDT. Herein, a nanoscale Co-ferrocene metal-organic framework (Co-Fc NMOF) with high Fenton activity is synthesized and combined with glucose oxidase (GOx) to construct a cascade enzymatic/Fenton catalytic platform (Co-Fc@GOx) for enhanced tumor treatment. In this system, Co-Fc NMOF not only acts as a versatile and effective delivery cargo of GOx molecules to modulate the reaction conditions, but also possesses excellent Fenton effect for the generation of highly toxic •OH. In the tumor microenvironment, GOx delivered by Co-Fc NMOF catalyzes endogenous glucose to gluconic acid and H 2 O 2 . The intracellular acidity and the on-site content of H 2 O 2 are consequently promoted, which in turn favors the Fenton reaction of Co-Fc NMOF and enhances the generation of reactive oxygen species (ROS). Both in vitro and in vivo results demonstrate that this cascade enzymatic/Fenton catalytic reaction triggered by Co-Fc@GOx nanozyme enables remarkable anticancer properties.

Delivery of therapeutics into the solid tumor microenvironment is a major challenge for cancer nanomedicine. Administration of certain exogenous enzymes which deplete tumor stromal components has been proposed as a method to improve drug delivery. Here we present a protein-free collagen depletion strategy for drug delivery into solid tumors, based on activating endogenous matrix metalloproteinases (MMP-1 and -2) using nitric oxide (NO). Mesoporous silica nanoparticles (MSN) were loaded with a chemotherapeutic agent, doxorubicin (DOX) as well as a NO donor (S-nitrosothiol) to create DN@MSN. The loaded NO results in activation of MMPs which degrade collagen in the tumor extracellular matrix. Administration of DN@MSN resulted in enhanced tumor penetration of both the nanovehicle and cargo (DOX), leading to significantly improved antitumor efficacy with no overt toxicity observed.

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