Cascade-reaction-triggered engineering nanocatalytic theranostics reconstructing tumor microenvironment through synergistic oxidative damage and aerobic glycolysis inhibition against colon cancer

• A pH/ROS responsive nanocatalytic theranostics realized on-demand cargo releasing. • The nano-platform reconstructed abnormal energy metabolism in tumor microenvironment. • The nanocatalyst triggered cascade processes in response to tumor microenvironment. • The integration of GOx, Fe 3 O 4 and RA-V achieved highly orchestrated cooperation. • The nano-platform realized remarkable anticancer activity in vitro and in vivo . Intratumoral glucose consumption-induced cancer starvation provides an emerging strategy for anticancer therapy, but encounters significant challenges as nonspecificity, adaptive development of parallel energy supplies and so on. Herein, the intelligent nanocatalytic theranostics (denoted as GOx/Fe 3 O 4 /RA NP) featured reactive oxygen species (ROS)-cleavable linker and pH-sensitive segment was designed, realizing the on-demand cargo releasing, and integration of glucose oxidase (GOx), Fe 3 O 4 and cyclopeptide RA-V with highly orchestrated cooperation. On one hand, as an efficient enzyme catalyst, GOx not only starved the tumor cells for achieving starvation therapy (ST), but also supplied gluconic acid for irritating drug release, simultaneously supplied H 2 O 2 for subsequent Fenton-like reaction mediated by Fe 3 O 4 . The generated hydroxyl radicals (•OH) catalyzed by Fe 3 O 4 effectively further accelerated decomposition of GOx/Fe 3 O 4 /RA NP, in addition to inducing tumor cells apoptosis and death for realizing the enhanced chemodynamic therapy (CDT). On the other hand, RA-V as a chemotherapeutic lead compound was also found to inhibit pivotal proteins involving in aerobic glycolysis pathway. The synergy between the GOx and RA-V exhibited a dual destruction in abnormal glucose metabolism through cutting off energy-supplying in cancer cell. As a result, the nano-platform (GOx/Fe 3 O 4 /RA NP) consisted of GOx-mediated ST, Fe 3 O 4 -elicited CDT, and RA-V-induced chemotherapy, demonstrated remarkable anticancer activity in vitro and in vivo , which provides the potential to develop mutual promotion strategy.