Synthesis of highly stable and emissive covalent organic frameworks (COFs) for biological applications is urgently needed. Herein, we developed a novel AIEgen-based sp 2 carbonconjugated COF (sp 2 c-COF) for activatable imaging and ferroptosis in target tumor cells. The sp 2 c-COF TFBE-PDAN was obtained by employing tetra-(4-aldehyde-(1,1-biphenyl)) ethylene (TFBE) as an AIEgen unit and 1,4-phenylenediacetonitrile (PDAN) as a linker through the Knoevenagel reaction. The asobtained COF TFBE-PDAN exhibited high chemical stability even in 3 M HCl and 3 M NaOH and 146-fold quantum yield enhancement compared with the corresponding imine-linked COF due to the C�C linkages and the AIEgens. The luminescence of COF TFBE-PDAN was dramatically quenched by a tannic acid (TA)based metal phenolic network (Fe III TA), which was formed via Fe(III)-directed metal−polyphenol coordination. After modified with polyethylenimine (PEI), COF TFBE-PDAN @Fe III TA-PEI was used for activatable imaging and ferroptosis. Fe III TA was dissociated in overexpressed glutathione (GSH) and the acidic lysosomal environment, which resulted in the recovery of luminescence and in situ Fe 2+ production. Overloaded H 2 O 2 in tumor cells could further react with Fe 2+ to produce reactive oxygen species (ROS) via the Fenton reaction. GSH depletion and ROS production led to lipid peroxide accumulation-mediated ferroptosis. The luminescence recovery of COF TFBE-PDAN also enabled it to act as a selfreporter for the decomposition of Fe III TA and imaging in tumor cells. This study shows that AIEgen-based sp 2 c-COF displays great potential for tumor cell imaging and therapy.

Distinguishing between normal, inflammatory, and progressing tumor cells plays a vital role in early diagnoses and clinical studies. The simultaneous quantification of multiple biomarkers in cells can reveal cellular heterogeneity, which contributes to the discrimination of different types of cells. Herein, a dual-channel fluorescent probe has been developed for monitoring peroxynitrite (ONOO–) and glutathione (GSH) to accurately discriminate normal cells, inflammatory cells, and progressing cancer cells. The probe can monitor exogenous and endogenous mitochondrial GSH and ONOO– in living cells and zebrafish by green (530 nm, G530) and red (630 nm, R630) emission based on its good selectivity and low biotoxicity. GSH and ONOO– are visualized via fluorescence imaging, and the corresponding output signals can be employed to differentiate nontumorigenic, malignant, and metastatic breast cells in cocultured cells. Furthermore, the accurate discrimination among normal, inflammatory, and cancerous cells is achieved through the changes in the dual-channel fluorescence signal, which shows great potential for the diagnosis of inflammation and cancer diseases.