A Membrane-Impermeable Near-Infrared Probe Enables High-Fidelity Tracking of Foam Cell Progression

Foam cell formation is a key pathological event in atherosclerosis, which can be used as an early diagnosis and drug selection platform for atherosclerotic disease. Current methods are hindered by an inability to distinguish pathological lipid aggregates in foam cells from normal lipid droplets in healthy macrophages in a live-cell context. Herein, we developed and synthesized a membrane-impermeable, near-infrared fluorescent probe named FMNIR-DBO for high-fidelity imaging of foam cell formation. The membrane impermeability was achieved by incorporating a charged, rigid moiety into a near-infrared D-π-A fluorophore, thereby enabling long-term anchoring to the plasma membrane in live cells. This probe uniquely exploits the loss of plasma membrane integrity that occurs as macrophages transform to foam cells. Consequently, FMNIR-DBO remains extracellular to healthy cells but selectively enters foam cells to illuminate pathological lipid aggregates, thereby eliminating interference from normal lipid droplets. This strategy enables rapid, dynamic imaging of lipid accumulation in living foam cells within 6 h, a 75% reduction in time compared to conventional Oil Red O staining. Furthermore, FMNIR-DBO was used to evaluate the cellular-level effects of ethanol on foam cell formation, providing robust evidence to support its role in excess-alcohol-induced atherosclerotic disease progression.