Abstract

Recent advances in nanomedicine have facilitated the development of potent nanomaterials with intrinsic enzyme-like activities (nanozymes) for cancer therapy. However, it remains a great challenge to fabricate smart nanozymes that precisely perform enzymatic activity in tumor microenvironment without inducing off-target toxicity to surrounding normal tissues. Herein, we report on designed fabrication of biodegradation-medicated enzymatic activity-tunable molybdenum oxide nanourchins (MoO3-x NUs), which selectively perform therapeutic activity in tumor microenvironment via cascade catalytic reactions, while keeping normal tissues unharmed due to their responsive biodegradation in physiological environment. Specifically, the MoO3-x NUs first induce catalase (CAT)-like reactivity to decompose hydrogen peroxide (H2O2) in tumor microenvironment, producing a considerable amount of O2 for subsequent oxidase (OXD)-like reactivity of MoO3-x NUs; a substantial cytotoxic superoxide radical (·O2-) is thus generated for tumor cell apoptosis. Interestingly, once exposed to neutral blood or normal tissues, MoO3-x NUs rapidly lose the enzymatic activity via pH-responsive biodegradation and are excreted in urine, thus ultimately ensuring safety. The current study demonstrates a proof of concept of biodegradation-medicated in vivo catalytic activity-tunable nanozymes for tumor-specific cascade catalytic therapy with minimal off-target toxicity.