MacroTAC: Synthetic macrophage-targeting chimeras for targeted degradation of extracellular Pathological cargos
Abstract
Targeted degradation strategies, such as PROTAC and LYTAC, have emerged as powerful tools for selective degradation of proteins or organelles. However, their applicability is restricted to intracellular cargos or limited number of extracellular proteins, leaving extracellular cargos such as pathogenic species, microbes, disease-associated protein aggregates, extracellular vesicles, cancer cells, and apoptotic cells, beyond the scope of these degraders. Here we developed MacroTAC (Macrophage-Targeting Chimera). a synthetic peptide-based platform designed to hijack the innate phagocytic capacity of macrophages for the clearance of cell-sized extracellular cargo. By engineering dual-headed peptides that simultaneously engage macrophage surface receptors (e.g., CD206) and disease-specific markers (e.g., calreticulin on apoptotic cells or EGFR on tumor cells), MacroTAC induces spatial proximity between macrophages and target cargo, thereby triggering precise and efficient phagocytosis. We validated this paradigm in two orthogonal disease models. In Dextran Sulfate Sodium Salt (DSS)-induced colitis, MacroTAC enhanced efferocytosis of apoptotic cells, reducing pathological burden and attenuating disease progression—an effect abolished in MerTK-deficient mice, confirming the dependence on canonical efferocytosis signaling. Crucially, single-cell RNA sequencing revealed that MacroTAC not only cleared cargo but also reprogrammed macrophages to remodel the immune microenvironment for sustainable therapeutic efficacy. In tumor xenografts, MacroTAC promoted macrophage-mediated phagocytosis of EGFR-high cancer cells, significantly suppressing tumor growth. By extending the induced-proximity principle beyond molecular degradation to cell-scale phagocytosis, MacroTAC establishes a versatile strategy for treating diseases driven by pathogenic extracellular cargo accumulation. This work bridges synthetic biology with innate immunity, offering a platform capable of targeting previously “undegradable” extracellular pathological structures.
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Declaration of Competing Interests
The authors declare no competing interests to disclose.
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