Macrophage-augmenting targeted chimaeras for extracellular protein degradation

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.