A Biomimetic MOF‐Based “Dual‐Stage Cumulative Activation” Autophagic Degradation System to Counter Tumor Recurrence Following Incomplete Radiofrequency Ablation of Hepatocellular Carcinoma
Abstract
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.
Article Details
Authors (13)
Yiqiao Wang
Department of Materials Science and Engineering, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong 999077, China
Zhihua Wang
School of Materials Science and Engineering, Tianjin Key Laboratory of Metal and Molecular Materials Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tongyan Road 38, Tianjin 300350, P. R. China
Yilin Yang
Mingda Han
State Key Laboratory of Inorganic Synthesis and Preparative Chemistry College of Chemistry Jilin University 2699 Qianjin Street Changchun 130012 China
Ying Yan
Xiaocheng Li
Department of Hepatobiliary and Pancreatic Surgery General Surgery Center The First Hospital of Jilin University 1 Xinmin Street Changchun 130021 China
Qiannan Miao
State Key Laboratory of Inorganic Synthesis and Preparative Chemistry College of Chemistry Jilin University 2699 Qianjin Street Changchun 130012 China
Xiuan Li
State Key Laboratory of Inorganic Synthesis and Preparative Chemistry College of Chemistry Jilin University 2699 Qianjin Street Changchun 130012 China
Jingying Wang
Zhan Shi
Xinlun Dai
Department of Hepatobiliary and Pancreatic Surgery General Surgery Center The First Hospital of Jilin University 1 Xinmin Street Changchun 130021 China
Fei Yan
Shouhua Feng
State Key Laboratory of Inorganic Synthesis and Preparative Chemistry College of Chemistry