Abstract

The pathogenesis of atherosclerosis involves a vicious cycle characterized by abnormal cholesterol crystals (CCs) accumulation, chronic inflammation, and endothelial dysfunction. CCs accumulation triggers chronic inflammation, which subsequently damages the endothelium, thereby exacerbating lipid leakage and further CCs deposition. Disrupting this pathological cycle is an urgent therapeutic challenge. Our study identified the cGAS-STING signaling pathway—known for mediating DNA immune sensing—as being closely associated with lipid deposition, endothelial dysfunction, and inflammation in atherosclerosis. Furthermore, we investigated the therapeutic potential of lipid micelles composed of lecithin and DSPE-PEG 2k conjugated with a CD47-targeting peptide. These micelles were loaded with methyl-β-cyclodextrin (MCD) and polyhistidine inclusion complexes (PLCH micelles) for dissolving CCs and treating atherosclerosis. PLCH micelles achieve targeted delivery to apoptotic foam cells via the CD47-targeting peptide. Under acidic conditions, polyhistidine undergoes protonation, weakening its interaction with MCD and facilitating the release of free MCD cavities. Crucially, the PLCH micelles demonstrated a dissolution efficacy for CCs 4.50 times greater than that of free MCD alone. When combined with the STING inhibitor C-176, this strategy remarkably restored endothelial tight junctions and glycocalyx structure, alleviated chronic inflammation, and effectively suppressed atherosclerosis progression. This combined therapy successfully disrupted the detrimental cycle of atherosclerosis development, and established a virtuous intervention cycle: lipid clearance promotes inflammation inhibition, which in turn fosters endothelial repair, and restored endothelium further enhances lipid clearance. This approach provides a novel therapeutic strategy for atherosclerosis treatment.