A Biomimetic MOF‐Based “Dual‐Stage Cumulative Activation” Autophagic Degradation System to Counter Tumor Recurrence Following Incomplete Radiofrequency Ablation of Hepatocellular Carcinoma

Abstract Incomplete RFA (iRFA) often leads to local tumor recurrence and metastasis in hepatocellular carcinoma (HCC). The m ⁶ A reader protein YTHDF1 plays an important role in this process. However, there are currently no effective YTHDF1‐specific inhibitors capable of overcoming tumor relapse following iRFA. This study successfully develops a “dual‐stage cumulative activation” autophagic degradation system based on a gallium MOF scaffold. The MOF are cloaked with HCC‐derived membranes, and a YTHDF1‐specific small molecule binder Y040 and the autophagy‐activating peptide Beclin‐1 are assembled through metabolic glycan engineering combined with click chemistry. GaMOF@M‐Beclin‐Y040 increases autophagic flux in the HCC cells by 7.1‐fold, and selectively degrades YTHDF1 with an efficiency of up to 92%. This in turn reduces m ⁶ A‐mediated transcript stability of EGFR and protein translation. Moreover, GaMOF@M‐Beclin‐Y040 could trigger immunogenic cell death of HCC cells. Across three distinct HCC tumor models, GaMOF@M‐Beclin‐Y040 effectively prevent local tumor recurrence post‐iRFA with an inhibition rate of 93.4%, synergized with anti‐PD‐1 antibody to suppress metastatic tumor growth by 96.6% after iRFA relapse, and induced durable immune memory that reduced the recurrence rate to 7.5%. This novel protein degradation platform can address tumor recurrence after iRFA, and potentially be applied to other oncogenic targets. Furthermore, it offers a conceptual framework for treating tumors harboring traditionally “undruggable” targets.