Recently, cyclodextrin (CD) has shown the potential for effective treatment of atherosclerotic plaques in mice by solubilizing plaque cholesterol. While promising as a new therapy for atherosclerosis, poor pharmacokinetics and ototoxicity of CD pose a therapeutic challenge. Thus far, however, there has been no attempts to overcome such limitations. Here, we showed that cyclodextrin polymer (CDP) with a diameter of similar to 10 nm exhibits outstanding pharmacokinetics and plaque targeting efficacy compared to a monomeric CD. Furthermore, we found out that CDP does not induce plasma membrane disruption as opposed to CD, which eliminated cytotoxicity and hemolytic activity of CD. In a mouse model of atherosclerosis, subcutaneous injections of beta-cyclodextrin polymer (beta CDP) significantly inhibited plaque growth compared to monomeric hydroxypropyl-beta-cyclodextrin (HP beta CD) at the same dose (1 g/kg). More importantly, beta CDP did not induce significant ototoxicity at a high-dose (8 g/kg) where HP beta CD reduced the outer hair cell content by 36%. These findings suggest that the polymerization of CD can overcome major limitations of CD therapy for treatment of atherosclerosis.