IRF5 siRNA Nanoimmunotherapy: Restoring Macrophage Efferocytosis in Atherosclerosis

BACKGROUND: Impaired efferocytosis of macrophages within advanced atherosclerotic plaques leads to plaque deposition and rupture, ultimately resulting in atherothrombotic events. Effective restoration of efferocytic capacity in lesional macrophages remains a challenge in atherosclerosis treatment. METHODS: We developed an engineered small interfering RNA (siRNA) nanoparticle platform that can therapeutically manipulate lesional macrophages by inhibiting an overexpressed plaque-destabilizing macrophage molecule: IRF5 . RESULTS: IRF5 siRNA (siIRF5) nanoimmunotherapeutics were efficiently taken up by lesional macrophages, particularly Cd11c + and Trem2 hi 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 evidenced by reduction of necrotic core area and enhancement of plaque stability in 2 independent ApoE −/− murine models of atherosclerosis. Single-cell RNA sequencing analysis revealed that siIRF5 nanoimmunotherapeutics increased the proefferocytic receptors while decreasing the expression of proinflammatory genes associated with cytokine and chemokine pathways in lesional macrophages. CONCLUSIONS: These findings highlight the potential of siRNA nanoimmunotherapeutics for treating atherosclerosis and other diseases resulting from impaired efferocytosis in macrophages.