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Early noninvasive screening and regression therapy for vulnerable atherosclerotic plaques remain challenging. In this study, it is aimed to develop a new approach for the active targeting of atherosclerotic plaques with nano‐agents to aid imaging and treatment. Biocompatible hyaluronic acid (HA)‐guided cerasomes are generated to selectively target CD44‐positive cells within the plaque in in vitro studies and in vivo testing in Apoe−/− mice. Rosuvastatin (RST) is encapsulated in the HA‐guided cerasome nano‐formulation to produce HA‐CC‐RST, which results in significant plaque regression as compared to treatment with the free drug. Moreover, gadodiamide‐loaded HA‐CC enhances magnetic resonance images of vulnerable plaques, thereby attaining the goal of improved simultaneous treatment and imaging. Transcriptomic analysis confirms plaque regression with HA‐CC–RST treatment, which potentially benefits from the anti‐inflammatory effect of RST. In summary, a safe and efficient nano‐formulation for the targeted delivery of active agents to atherosclerotic plaques is developed and may be applicable to other diagnostic and therapeutic agents for atherosclerosis treatment. [ABSTRACT FROM AUTHOR]