Overcoming Chemoresistance via an AIEgen-Based Covalent Organic Framework.

Chemoresistance remains a major barrier to effective cancer treatment, leading to tumor recurrence and high mortality. Developing strategies to combat chemoresistant tumors is therefore an urgent challenge. Here, we report a covalent organic framework (COF) nanomedicine, 3N-DPQ-COF, designed to target chemoresistant cancers. Mechanistic studies reveal that 3N-DPQ-COF accumulates efficiently in resistant tumor cells and suppresses cancer stemness in 4T1 and CT26 models, outperforming doxorubicin. Moreover, 3N-DPQ-COF promotes CD8+ T-cell infiltration and reduces the number of immunosuppressive erythroid progenitor cells and myeloid-derived suppressor cells, thereby remodeling the tumor microenvironment (TME) and inducing GSDME-dependent pyroptosis. Remarkably, even without checkpoint blockade, 3N-DPQ-COF suppresses metastasis and recurrence in chemoresistant 4T1 tumors, achieving >90% tumor inhibition and cure rates exceeding 80%. This study highlights the potential of AIEgen-based COF nanomedicines for overcoming chemoresistance through concurrent modulation of tumor stemness, pyroptosis, and immune activation.