Synthetic cleavage-resistant TREM2 boosts macrophage efferocytosis to treat inflammatory diseases.

Triggering receptor expressed on myeloid cells 2 (TREM2), a critical sensor of cell debris, regulates macrophage efferocytosis to maintain tissue immune homeostasis. However, inflammatory mediators upregulate the sheddase ADAM17, leading to TREM2 cleavage, which impairs apoptotic cell clearance and exacerbates inflammation. We here report a synthetic cleavage-resistant TREM2 (CRT) to boost TREM2-dependent efferocytosis and alleviate inflammation associated with aberrantly accumulated apoptotic cells. CRT integrates the ligand-binding domain of TREM2 with its intracellular signaling adaptor DAP12 via a custom-engineered stalk and transmembrane segment. Our data demonstrate that CRT amplifies TREM2 signaling even in the presence of ADAM17. Customized lipid nanoparticles efficiently introduce CRT mRNA into macrophages, generating CRT-engineered macrophages (CRT-Ms) in situ. CRT-Ms effectively reduce apoptotic cell burden and alleviate inflammation in mouse models of metabolic-dysfunction-associated steatohepatitis and atherosclerosis. In sum, our findings establish that CRT strengthens TREM2-mediated macrophage efferocytosis and mitigates inflammation, with broad potential for apoptotic-cell-associated diseases.