IRF5 siRNA Nano-Immunotherapy: Restoring Macrophage Efferocytosis in Atherosclerosis

We observe that the siIRF5 nano-immunotherapeutics were efficiently taken up by lesional macrophages, particularly Cd11c+ and Trem2hi macrophages, and enhanced their phagocytic clearance of apoptotic cells by efficiently silencing IRF5 expression within these macrophage subsets in atherosclerotic plaques. This resulted in remarkable therapeutic efficacy, as evidence by reduction of necrotic core area and enhancement of plaque stability in two independent ApoE-/- murine models of atherosclerosis. Mechanistically, single-cell RNA sequencing analysis revealed that siIRF5 nano-immunotherapeutics increased the pro-efferocytic receptors while decreasing the expression of pro-inflammatory genes associated with cytokine and chemokine pathways in lesional macrophages. Overall design: We conducted single-cell RNA sequencing (scRNA-seq) to explore the molecular impact of ZnDPA@siIRF5 treatment on lesional macrophages in the aorta.