Piperazine-Structured Lipid Nanoparticles Enable Enhanced Targeted Delivery of SHP-1 siRNA to Macrophages for Treatment of Atherosclerotic Vulnerable Plaques

Abstract Atherosclerotic vulnerable plaques pose a risk for acute coronary syndrome and sudden cardiac death due to plaque rupture and thrombosis. While nanomedicines modulating macrophage functions have attracted intensive interest, efficient delivery to plaque macrophages remains challenging. Here, mannose-modified lipid nanoparticles (LNPs) are developed for targeted delivery of a novel SHP-1 (Src Homology 2 Domain-containing Phosphatase-1) siRNA to macrophages within atherosclerotic vulnerable plaques, aiming to enhance macrophage function and stabilize plaques. In ApoE–/– mice with vulnerable plaques, both MIC5 and SM-102 LNPs demonstrated robust plaque targeting capabilities (Cy5 fluorescence reaching ∼1010 p/sec/cm2/sr) and significantly reduced plaque area following SHP-1 siRNA delivery. Importantly, the piperazine-based MIC5 LNPs exhibited enhanced plaque targeting efficiency with M2 macrophage uptake efficiency reaching 46.32% as well as superior therapeutic effects. Collectively, these SHP-1 siRNA-loaded LNPs offer a promising targeted therapeutic strategy for atherosclerotic vulnerable plaques and establish a novel nanoplatform for RNA-based macrophage-modulation in various inflammatory diseases.