Thioguanine-Coordinated Assembly for Synthetic Lethality of Colorectal Cancer with Defective Mismatch Repair

Abstract

A thioguanine-coordinated metal-organic polymer was designed for the carrier-free co-delivery of thioguanine and Werner syndrome helicase (WRN) inhibitor to induce synthetic lethality in colorectal cancer cells with defective mismatch repair. Upon glutathione-triggered disassembly of the nanovector, the released thioguanine and WRN inhibitor concurrently disrupted both primary and compensatory DNA damage response pathways, achieving significant synthetic lethality.