A Plug‐and‐Play Ferritac Platform Degrading Membrane Proteins via Receptor Crosslinking

Abstract Membrane protein degradation techniques hijacking lysosome targeting receptors (LTRs) have provided new opportunities to develop anticancer therapeutics. However, due to varied expression of these LTRs and potential influence on their native biological function resulting from excessive endocytosis, developing alternative membrane protein degraders is highly desirable. Here, Ferritac (ferritin‐based targeting chimeras) is developed, a plug‐and‐play membrane degradation platform that displayed multivalent antibodies via Spycatcher‐Spytag chemistry to crosslink the membrane protein ectodomains nearby for degradation. Based on receptor crosslinking, the Ferritac platform obviates the dependence on specific LTRs. This study reveals the Ferritac nanoparticles efficiently degraded epidermal growth factor receptor (EGFR) both in vitro and in vivo. In mechanistic studies, the Ferritac‐Anti‐EGFR nanoparticles adopted clathrin‐based endocytosis and mainly involved with lysosome pathways for protein degradation, which are successfully expanded to degrade PD‐L1 (programmed death‐ligand 1) and HER2 (human epidermal growth factor receptor 2) in vitro. Moreover, the efficient PD‐L1 degradation by Ferritac‐Anti‐PD‐L1 to induce a potent anticancer immune response in vivo is validated in both MC38 and B16F10 tumor models. Further combined with chemotherapeutics paclitaxel, the Ferritac‐Anti‐PD‐L1 saw a satisfactory synergistic therapeutic effect. Overall, the Ferritac platform could be easily applied to various targets by directly attaching the relevant antibodies and could be a promising candidate as a novel and versatile LTR‐independent membrane protein degrader.