<i>IRF5</i> siRNA Nanoimmunotherapy: Restoring Macrophage Efferocytosis in Atherosclerosis.

Abstract

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. We developed an engineered small interfering RNA (siRNA) nanoparticle platform that can therapeutically manipulate lesional macrophages by inhibiting an overexpressed plaque-destabilizing macrophage molecule: <i>IRF5</i>. <i>IRF5</i> 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 <i>IRF5</i> 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 <i>ApoE</i>^-/- 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. These findings highlight the potential of siRNA nanoimmunotherapeutics for treating atherosclerosis and other diseases resulting from impaired efferocytosis in macrophages.