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<p>Lysosome-targeting chimeras (LYTACs) hold therapeutic potential by degrading pathogenesis-associated proteins. However, current LYTAC systems often require considerable effort for case-by-case construction and are devoid of a convenient and efficient modular platform. Here, we develop a modular LYTAC platform based on human heavy chain ferritin (HFn), leveraging its peptide-display function and TfR1-mediated lysosomal endocytosis. This system comprises a bioengineered HFn scaffold with enhanced TfR1 affinity and target-specific affibodies conjugated to the HFn via SpyTag-SpyCatcher system. Using this approach, HFn-LYTACs efficiently degrade epidermal growth factor receptor, epidermal growth factor receptor-2 and programmed death-ligand 1. Mechanistic studies indicate that the HFn-LYTAC platform mediates the degradation of membrane proteins via two distinct mechanisms: a TfR1-dependent endocytic pathway as well as the nanoparticle size and multivalent ligand effect of HFn-LYTAC. In vivo, HFn-LYTACs inhibit tumor growth with favorable safety. Therefore, the modular HFn-LYTAC platform represents a versatile, efficient, and promising strategy for tumor-targeted therapy.</p>

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Bioengineered ferritin-based lysosome-targeting chimera platform for tumor-targeted therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月9日

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  • Shuai Zhang,
  • Yiliang Jin,
  • Yaxin Hou,
  • Guoheng Tang,
  • Zhuoran Wang,
  • Xuehui Chen,
  • Xiyun Yan,
  • Kelong Fan

摘要

Lysosome-targeting chimeras (LYTACs) hold therapeutic potential by degrading pathogenesis-associated proteins. However, current LYTAC systems often require considerable effort for case-by-case construction and are devoid of a convenient and efficient modular platform. Here, we develop a modular LYTAC platform based on human heavy chain ferritin (HFn), leveraging its peptide-display function and TfR1-mediated lysosomal endocytosis. This system comprises a bioengineered HFn scaffold with enhanced TfR1 affinity and target-specific affibodies conjugated to the HFn via SpyTag-SpyCatcher system. Using this approach, HFn-LYTACs efficiently degrade epidermal growth factor receptor, epidermal growth factor receptor-2 and programmed death-ligand 1. Mechanistic studies indicate that the HFn-LYTAC platform mediates the degradation of membrane proteins via two distinct mechanisms: a TfR1-dependent endocytic pathway as well as the nanoparticle size and multivalent ligand effect of HFn-LYTAC. In vivo, HFn-LYTACs inhibit tumor growth with favorable safety. Therefore, the modular HFn-LYTAC platform represents a versatile, efficient, and promising strategy for tumor-targeted therapy.