A Biomimetic MOF-Based "Dual-Stage Cumulative Activation" Autophagic Degradation System to Counter Tumor Recurrence...

Incomplete RFA (iRFA) often leads to local tumor recurrence and metastasis in hepatocellular carcinoma (HCC). The m⁶A 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 m⁶A-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.