International Immunopharmacology · Jul 30, 2026

Dual restoration of TGFβ1 and MerTK in macrophages alleviates atherosclerosis via enhanced efferocytosis and anti-inflammatory polarization

By Wang T, Cheng H, Zhang T et al.

BACKGROUND & AIMS: Although metabolic dysfunction-associated steatotic liver disease and atherosclerosis frequently coexist, no therapy concurrently targets both conditions. We previously observed that in such comorbidity settings, macrophages exhibit impaired efferocytosis and reduced anti-inflammatory polarization. In this study, we investigated whether simultaneously restoring these two defective macrophage functions could provide a unified therapeutic strategy both for hepatic and vascular pathology. METHODS: To establish a comorbidity model featuring concurrent hepatic steatosis and atherosclerosis, we fed ApoE-/-mice a high-fat diet for 14 weeks. Moreover, we engineered bone marrow-derived macrophages to co-overexpress TGFβ1 and MerTK (MφSmart), thereby restoring anti-inflammatory properties and phagocytic capacity, then treated mice with control macrophages or MφSmart. RESULTS: TGFβ1 and MerTK overexpression in macrophages reprogrammed these cells toward an anti-inflammatory phenotype and endowed them with strong phagocytic capacity under lipid-loaded conditions. MφSmart reprogrammed macrophage injection into ApoE-/- mice alleviated inflammation locally in the plaque and liver. Consistent with the reduced inflammation, plaques became smaller and more stable after the adoptive transfer of reprogrammed macrophages. Mechanistically, the reprogrammed macrophages alleviated disease manifestations not only via direct inhibition of plaque inflammation but also by reshaping the inflammatory condition in the liver and plaque, where the transferred MφSmart predominantly accumulated. CONCLUSIONS: Macrophage-targeted dual-gene therapy overcomes the limitations of single-target approaches and achieves simultaneous therapeutic efficacy both in the liver and vasculature, establishing a preclinical proof-of-concept for multi-gene synergistic cell therapy in cardiometabolic disease.

doi.org/10.1016/j.intimp.2026.117180Open access, accepted manuscriptPubMed 42531783Interventions