Targeted Delivery of GLUT1 Inhibitor via Macrophage Nanovesicles for Pulmonary Arterial Hypertension Therapy

ABSTRACT Pulmonary arterial hypertension (PAH) is a lethal disease characterized by inflammation‐driven vascular remodelling, with a lack of precise intervention strategies targeting pro‐inflammatory M1 macrophages' glycolytic metabolic reprogramming. This study introduced Mac@WZB117, a macrophage membrane‐camouflaged nanovesicle delivering the GLUT1 inhibitor WZB117, specifically targeting M1 macrophages for PAH treatment. In mouse models of PAH induced by MCT and SU5416 combined with hypoxia, Mac@WZB117 effectively targeted pulmonary vascular lesions, leading to a significant reversal of arterial thickening and collagen deposition. Molecular analyses indicated a downregulation of GLUT1 expression in M1 macrophages, along with a polarization shift from M1 to M2. Furthermore, intervention with Mac@WZB117 reshaped the immuno‐metabolic lineage by inhibiting glycolysis, lipid metabolism and TGF‐β signalling pathways. Spatial transcriptomics analysis confirmed the spatial reorganization of hyperactive M1 macrophages from lesion regions. Overall, Mac@WZB117 delivers WZB117 precisely to M1 macrophages, suppressing their pro‐inflammatory and metabolic functions to remodel the immune microenvironment and reverse vascular structural changes, suggesting a promising therapeutic approach for PAH and other immuno‐metabolic diseases.