Abstract

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. Lysosome-targeting chimeras (LYTACs) hold therapeutic potential by degrading pathogenesis associated proteins, but current LYTAC systems often require case-by-case constructions and are devoid of a convenient and efficient modular platform. Here, the authors address these issues by developing a modular ferritin-based LYTAC platform for targeted degradation of membrane proteins for cancer therapy.