The synergistic therapy combining Cu2-xSe/ZIF-8 nanoparticles with crizotinib for the treatment of colorectal cancer

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide, yet chemotherapy resistance, tumor recurrence, and systemic toxicity limit current therapies. Here, we developed a multimodal Cu 2-x Se@ZIF-8-crizotinib (CSZC) nanoplatform that integrates chemosensitization, photodynamic therapy (PDT), and self-sustaining chemodynamic therapy (CDT). The core–shell structure, consisting of ultrafine Cu 2-x Se nanocrystals confined within a ZIF-8 framework, enables efficient crizotinib loading through mesoporous confinement and π-π interactions. Under near-infrared (808 nm) irradiation, photocatalysis converts O 2 into cytotoxic singlet oxygen ( 1 O 2 ), inducing mitochondrial dysfunction and DNA damage. Meanwhile, the acidic tumor microenvironment triggers ZIF-8 degradation, promoting Cu + /Cu 2+ -mediated Fenton-like conversion of H 2 O 2 into hydroxyl radicals (·OH). Concurrently, released crizotinib inhibits ALK/ROS1 signaling and enhances ROS-induced endoplasmic reticulum stress, forming a drug-sensitization/ROS-amplification feedback loop. This PDT-CDT-chemotherapy synergistic strategy provides an effective approach to enhance chemosensitivity and antitumor efficacy in CRC.