Dual‐Targeted Type‐I‐Photosensitizer‐Incorporated Covalent Organic Frameworks Overcome Hypoxia Barriers in Hepatocellular Carcinoma for Precision Therapy

ABSTRACT There is an urgent need to develop innovative therapeutic strategies for hepatocellular carcinoma (HCC) treatment with severe hypoxia. Covalent organic frameworks (COFs) hold promise for photodynamic therapy (PDT), yet their antitumor efficacy is limited by the hypoxia intolerance of type II PDT. Herein, we report a COF‐based nanoplatform grafted with type I photosensitizer (Enbs‐Ar‐NH 2 ) and co‐loaded with lenvatinib (Len) and curcumin (Cur), enabling concurrent type I PDT and chemotherapy (CT). The platform is conjugated with galactose (GalNAc) and RGD peptides, denoted as LC@GR‐COF‐E, which achieves dual‐targeting toward hepatocytes via ASGPR recognition and tumor‐associated endothelia binding. In vitro results demonstrate that the combination of Len and Cur effectively suppresses tumor cell proliferation. Importantly, LC@GR‐COF‐E can be activated to eradicate hypoxic tumor cells via oxygen‐independent type I PDT under NIR irradiation. LC@GR‐COF‐E/NIR exhibits potent anti‐metastatic effects, particularly against HCC cancer stem cell‐like cells (C5WN1), by downregulating MMP‐2 and MMP‐9 and modulating epithelial‐mesenchymal transition (EMT)‐related protein expression (N‐cadherin). In a subcutaneous C5WN1 hypoxic tumor‐bearing mouse model, the platform achieves a tumor inhibition rate of 95.5% ± 1.7%, offering a powerful strategy to overcome HCC hypoxia barriers. Our work pioneers a COF‐based type I PDT platform for precise therapy against hypoxic HCC.