Bioengineered ferritin-based LYTAC platform for tumor-targeted therapy

Lysosome-targeted chimeras (LYTACs) have emerged as promising therapeutic agents because of their ability to degrade pathogenesis-related proteins. However, the current LYTAC systems often require considerable effort for individual construction and are devoid of a convenient and efficient modular platform. Here, we developed a modular human heavy chain ferritin (HFn)-based LYTAC platform by harnessing its unique protein cage structure and its capacity for endocytosis into lysosomes via tumor-specific overexpression of transferrin receptor 1 (TfR1). This LYTAC platform consists of two components: a bioengineered HFn-based scaffold with optimized binding affinity for TfR1 and an affibody against a protein of interest (POI), which can be conveniently and stably conjugated through the SpyTag-SpyCatcher system. A series of HFn-LYTACs were constructed with the capacity to efficiently degrade different POIs, including epidermal growth factor receptor, epidermal growth factor receptor-2 and programmed death-ligand 1. Further investigations indicated that the HFn-LYTAC platform mediated the degradation of POI through two distinct mechanisms: a TfR1-dependent endocytic pathway and multivalent interactions between HFn-LYTAC and POI. In vivo experiments demonstrated that HFn-LYTACs effectively inhibited tumor progression while maintaining favorable biosafety profiles. Therefore, the modular HFn-LYTAC platform represents a versatile, efficient, and promising strategy for tumor-targeted therapy.