Zwitterionic Supramolecular Nanoassemblies With siRNA and Simvastatin as “Nanoscavenger” for Synergistic Atherosclerosis Treatment

Abstract Atherosclerotic vulnerable plaques contain various undesirable components, including excess cholesterol, efferocytosis‐deficient macrophages, and inflammatory factors. However, conventional lipid‐lowering drugs often show limited efficacy due to their inability to target the complex pathophysiology. Herein, innovative zwitterionic supramolecular nanoassemblies, termed PCDSC‐S2P, are developed as the nanoscavenger to reduce and stabilize plaques. The nanoassemblies are based on zwitterionic poly(carboxybetaine)‐modified β‐cyclodextrin (β‐CD) acting as a host molecule that encapsulates simvastatin (Sim) as a guest and absorbs small interfering RNA targeting calcium/calmodulin‐dependent protein kinase II gamma (siCaMKIIγ) electrostatically. The PCDSC‐S2P nanoassemblies are driven by host‐guest interactions, electrostatic interactions, and hydrogen bonds. Moreover, the macrophage‐targeting peptide modification directs nanoassemblies accumulation toward atherosclerotic plaques. Therefore, PCDSC‐S2P, as the nanoscavenger, can act at the lesional plaque via β‐CD‐mediated cholesterol removal, Sim‐driven lipid lowering, and siCaMKIIγ‐enhanced efferocytosis synergistically. Consequently, the PCDSC‐S2P treatment regulates the release of inflammatory cytokines and exhibits anti‐inflammatory activity. Furthermore, PCDSC‐S2P can significantly reduce plaque area and stabilize plaques in apolipoprotein E‐deficient mice fed with a high‐fat diet. Together, PCDSC‐S2P shows great potential as a new delivery system in the development of small interfering RNA formulation, showing its promise for atherosclerosis treatment.