Cholesterol-Mediated Protein Corona Controls in Vivo Clearance and Selective Organ Distribution of Liposomes

Cholesterol is a key determinant of membrane stability and fluidity in both natural and synthetic lipid systems. Although widely used, its content varies greatly among commercial liposomes, and its regulatory effects on biological interactions remain insufficiently understood. Here, we reveal that cholesterol content critically governs the protein corona composition and binding affinity of liposomes, thereby dictating their cellular interactions and in vivo fate. Complement proteins exhibit a biphasic adsorption pattern that modulates monocyte and Kupffer cell uptake and systemic clearance. High cholesterol levels enrich apolipoproteins, particularly ApoE, promoting hepatocyte targeting, liver accumulation, and enhanced uptake by dendritic cells in blood and spleen. In contrast, low-cholesterol liposomes form albumin-dominated coronas that favor uptake by liver sinusoidal and pulmonary endothelial cells, leading to preferential lung accumulation. Notably, cholesterol-rich liposomes significantly suppress hepatocellular carcinoma progression through improved liver targeting and prolonged circulation. These findings identify cholesterol as a pivotal regulator of serum protein interactions and biodistribution, providing valuable insights for the rational design of efficient, organ-specific liposomal drug delivery systems.