Macrophage-augmenting targeted chimaeras for extracellular protein degradation

Extracellular targeted protein degradation (eTPD) systems typically function through passive endocytic trafficking mechanisms that direct extracellular proteins toward lysosomal degradation without actively modulating the functional state of the target cell. Here we report macrophage-augmenting targeted chimaeras (MATACs), a dual-effector eTPD platform inspired by macrophage-mediated efferocytosis. MATACs are constructed by conjugating target-binding antibodies with synthetic polyphosphoserine (PPS) polymers that mimic the polyvalent phosphatidylserine "eat-me" signals displayed on apoptotic cells. We show that PPS functions as a programmable macrophage-targeting ligand that induces macrophage-specific uptake, lysosomal activation, and M2-like immune repolarization. By leveraging this biology, MATACs simultaneously direct extracellular and membrane-associated proteins toward macrophage lysosomes for degradation while actively reprogramming the engulfing macrophages into enhanced degradative and anti-inflammatory states. We show that MATACs efficiently degrade multiple inflammatory targets, including tumor necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), matrix metalloproteinase-9 (MMP-9), CD86, and CD40. Mechanistically, PPS engagement promotes feed-forward enhancement of macrophage phagocytic and lysosomal functions, establishing a self-amplifying degradation cascade distinct from existing eTPD systems. In murine models of rheumatoid arthritis and ulcerative colitis, TNF-alpha-targeted MATACs exhibit potent therapeutic efficacy, superior suppression of inflammatory signaling, and restoration of immune homeostasis relative to the conventional neutralizing antibody. Collectively, these findings establish MATACs as the first dual-effector extracellular degrader platform in which the effector ligand itself actively reprograms the degradative immune cell during target elimination.