Engineered Lysosome-Targeted Protein Degradation via Hijacking Macropinocytosis

Recently, targeted protein degradation (TPD) strategies have emerged as an effective tool for addressing undruggable targets in both biomedical research and the pharmaceutical industry, selectively binding proteins of interest and targeting them to the intracellular degradation machinery for degradation. However, the targeting of extracellular proteins with current degradation tools requires a tedious, case-specific selection and design process based on lysosomal trafficking of cell surface receptors. Here, we introduce Macropinocytosis-Targeting Chimeras (MapTACs), a TPD platform that exploits macropinocytosis, a receptor-independent endocytic process, to deliver extracellular proteins to lysosomes for degradation. Using dextran as a versatile scaffold conjugated to protein-binding aptamers or antibodies, we demonstrate that MapTACs efficiently degrade monocyte chemotactic protein-1 (MCP-1) in a time-, dose-, and macropinocytosis-dependent manner. Importantly, without the need for receptor-specific modifications, MapTACs exhibit broad applicability to a variety of cell types and extracellular protein targets (MCP-1, tumor necrosis factor-α, and interferon-γ). In vivo, TNF-α-targeting MapTACs effectively and specifically reduce the levels of TNF-α in an LPS-induced acute inflammation model, attenuating lung injury, with a half-life of approximately 0.72 h and predominant accumulation in the liver and lung, where F4/80-positive monocytes/macrophages serve as the primary uptake cells. By overcoming the limitations of the receptor-based TPD strategy, MapTAC provides a universal, cost-effective, and scalable platform for extracellular protein degradation, facilitating the development of targeted protein degradation tools and opening opportunities for therapeutic intervention in cancer, inflammation, and other diseases.