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

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.