Abstract
Hypoxia, a prevalent characteristic of solid tumors, substantially impairs the efficacy of cancer treatments. However, there are no feasible clinical approaches for treating hypoxic tumors. Here, we develop metal-phenolic networks (CuGI) utilizing the natural glycolysis inhibitor (epigallocatechin gallate) and the essential metal element in the human body (copper ions), specifically targeting and annihilating hypoxic cancer cells. CuGI redirects the metabolic pathway of hypoxic cancer cells from anaerobic glycolysis to oxidative phosphorylation, thereby enhancing reactive oxygen species production and promoting oligomerization of lipoylated proteins in the tricarboxylic acid cycle. Through targeted induction of oxidative and proteotoxic stresses, CuGI induces apoptosis and cuproptosis specifically in cancer cells under hypoxic conditions while sparing normal cells. Moreover, cancer cell membrane-coated CuGI (CuGI@CM) exhibits enhanced tumor penetration effect and demonstrates commendable biocompatibility, effectively suppressing colorectal tumor growth. Importantly, CuGI@CM, when combined with vascular disruptors or radiotherapy which aggravate tumor hypoxia, synergistically potentiates therapeutic efficacy. Thus, CuGI represents a specific and potent nanotherapeutic capable of selectively eliminating hypoxic tumors, offering promise in combination therapies to address tumor hypoxia.