A Copper−Organic Framework Nanozyme Exposes Mitochondrial Vulnerability to Enhance Colorectal Cancer Chemosensitivity

Abstract

Colorectal cancer (CRC) frequently acquires resistance to cytotoxic chemotherapy through adaptive mitochondrial programs that buffer oxidative stress and elevate the apoptotic threshold. Here, we report a therapeutic strategy that exploits copper-dependent mitochondrial stress associated with cuproptosis to destabilize this adaptive resilience and lower the barrier for chemotherapy-induced cytotoxicity. We engineered a copper incorporated zeolitic imidazolate framework (Cu-ZIF) nanozyme that performs dual redox catalysis: a Cu+ mediated Fenton like reaction generates hydroxyl radicals, while GPX4 mimetic activity depletes glutathione, collectively dismantling antioxidant defenses. Upon tumor cell internalization, Cu-ZIF releases bioavailable copper, eliciting cuproptosis-associated mitochondrial stress characterized by DLAT oligomerization, downregulation of the lipoylation regulators FDX1 and LIAS, loss of iron−sulfur cluster proteins, and collapse of mitochondrial membrane potential. This preexisting organelle destabilization sensitizes CRC cells to doxorubicin, converging copper dependent proteotoxicity with DNA damage and oxidative stress to amplify intrinsic apoptotic signalling. In a syngeneic CT26 mouse model, combined Cu-ZIF and doxorubicin treatment produced marked tumor suppression without dose escalation. These findings establish targeted copper delivery as a means to convert mitochondrial adaptation from a survival mechanism into a therapeutic vulnerability, providing a mechanistic basis for enhancing chemosensitivity in solid tumors.