Reprogramming Lesional Macrophage Homeostasis via Interferon Regulatory Factor 5 Targeted siRNA Nanoimmunotherapy for Atherosclerosis

Atherosclerotic macrophages predominantly exhibit a pro-inflammatory phenotype, driving chronic inflammatory and accelerating atherosclerotic progression. Interferon regulatory factor 5 (IRF5) is highly expressed in lesional macrophages within advanced atherosclerotic plaques, where it promotes the secretion of pro-inflammatory cytokines. However, current approaches lack an effective therapeutic strategy to specifically silence this gene in lesional macrophages for atherosclerosis treatment. This study aims to develop and evaluate a dual-targeted, siRNA-based nanotherapeutic platform that selectively acts on atherosclerosis-promoting genes in plaque macrophages, offering a potential strategy for treating atherosclerosis by reprogramming lesional macrophages. Here we designed and developed dual-targeted liposome-based nano-immunotherapeutics encapsulating small interfering RNA (siRNA) against IRF5 (siIRF5) to reprogram macrophage phenotypes within advanced plaques. In high-fat diet-fed <i>ApoE</i>^-/- mice with advanced atherosclerotic plaques, dual-targeted siIRF5-loaded liposomes effectively accumulate within lesional macrophages, downregulate IRF5 expression, and promote anti-inflammatory macrophage polarization. Moreover, this siIRF5-based nanoimmunotherapy significantly reduces plaque burden and enhances plaque stability in two independent murine models of atherosclerosis. Furthermore, this siIRF5 nanoimmunotherapy exhibits biocompatibility even after long-term administration, underscoring its translational potential for clinical application in atherosclerosis treatment. This study introduces an innovative dual-targeted siRNA-based nanotherapeutic strategy that acts on atherosclerosis-promoting genes in plaque macrophages, offering a promising therapeutic avenue for atherosclerosis and other macrophage-driven inflammatory diseases.