Enhanced Cholesterol Efflux and Atherosclerosis Regression via CEH Gene Delivery Using Galactose-Functionalized Dendrimeric Nanoparticles

Cholesteryl ester hydrolase (CEH) is a critical enzyme in cholesterol ester hydrolysis, influencing cholesterol metabolism and efflux. This study demonstrates that CEH overexpression promotes free cholesterol efflux from macrophages, thereby reducing the lipid burden in existing atherosclerotic plaques. To enable targeted delivery, galactose-functionalized polyamidoamine (PAMAM) dendrimeric nanoparticles were utilized as nanocarriers for hepatic delivery of the CEH expression vector. The therapeutic potential of CEH plasmid-loaded dendrimeric nanoparticles was evaluated in Ldlr^-/- mice. Results showed a significant reduction in total lesion area (21%) and aortic arch lesion area (23%) compared to baseline. Lesion component analysis revealed marked decreases in total cholesterol (36%), free cholesterol (35%), and cholesterol esters (44%). Collectively, these results support CEH overexpression as an effective strategy to enhance cholesterol efflux and mitigate lipid accumulation in atherosclerotic plaques. Moreover, galactose-functionalized PAMAM dendrimeric nanoparticles demonstrate strong potential as a targeted hepatic gene delivery system for therapeutic intervention in atherosclerosis.