biostudies-literatureUnknown7(2)Dong XDepartment of Science and Technology of Shandong ProvinceNational Natural Science Foundation of ChinaTriggering 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 introduceCell reports. Medicine102580https://www.ebi.ac.uk/biostudies/studies/S-EPMC12923966biostudies-literatureSynthetic cleavage-resistant TREM2 boosts macrophage efferocytosis to treat inflammatory diseases.PMC12923966Li CDong XBo LGao JSun WZhao XLi NZhi YLiu ZJiang XKong ZXu XXiu QZhao KLou JSong YfalseSynthetic 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 introduce2026-01-01T00:00:00Z2026 Feb2026-07-16T15:14:22.012Z2026-07-10T03:09:31.412ZS-EPMC129239664161676410.1016/j.xcrm.2025.102580