Macropinocytosis-mediated recyclable LYTACs (McR-TACs) for receptor-independent protein degradation.

The degradation of cell membrane and extracellular proteins with lysosome-targeting chimeras (LYTACs) is limited by nonrecyclable, receptor-dependent mechanisms that shuttle proteins to lysosomes, restricting the broad use of this emerging technology. Here we developed a recyclable chimera composed of a polyzwitterion and protein of interest (POI) ligand for protein degradation. This chimera could interact with the cell membrane to trigger macropinocytosis together with the POI in a receptor-independent manner. Furthermore, it can dissociate from the POI in the acidic endocytic compartments and subsequently be exocytosed through the endoplasmic reticulum-Golgi transcytosis pathway. Ultimately, the exocytotic chimera initiates the next round of targeted protein degradation. These macropinocytosis-mediated recyclable LYTACs (McR-TACs) durably degrade the cell membrane protein (programmed cell death ligand 1) or the extracellular protein (macrophage migration inhibitory factor) in a triple-negative breast cancer mouse model, thereby inhibiting the tumor growth. Collectively, McR-TACs show the potential of leveraging natural transport pathways to create recyclable protein degraders with wide-ranging applications.