A Calixsalan-based ionizable lipid for macrophage-targeted Trem2 siRNA delivery attenuates atherosclerosis.

Targeting plaque macrophages with siRNA is a promising therapeutic strategy for atherosclerosis, but effective in vivo delivery remains a major challenge. Here, we introduce a therapeutic platform based on a novel ionizable lipid derived from a Calixsalan macrocycle. This lipid enables the formulation of macrophage-targeted lipid nanoparticles (LNPs) for potent siRNA delivery. We validated this platform by targeting Trem2, a receptor implicated in atherogenesis. Our study also reveals that circulating soluble Trem2 (sTrem2) is an independent clinical predictor of coronary artery disease. Mechanistically, we show that macrophage promotes vascular smooth muscle cells proliferation and migration via secretion of PDGF-BB in a KLF4-dependent manner. In an atherosclerotic mouse model, intravenous administration of our targeted LNPs successfully silenced macrophage Trem2, suppressed pro-atherogenic pathways, and significantly attenuated plaque burden. This work establishes Trem2 silencing as a viable therapeutic strategy and presents a new, rationally designed macrocyclic lipid platform for targeted nucleic acid delivery.